Showing papers by "University of Washington published in 1973"

Ionic Blockage of Sodium Channels in Nerve

Abstract: Increasing the hydrogen ion concentration of the bathing medium reversibly depresses the sodium permeability of voltage-clamped frog nerves. The depression depends on membrane voltage: changing from pH 7 to pH 5 causes a 60% reduction in sodium permeability at +20 mV, but only a 20% reduction at +180 mV. This voltage-dependent block of sodium channels by hydrogen ions is explained by assuming that hydrogen ions enter the open sodium channel and bind there, preventing sodium ion passage. The voltage dependence arises because the binding site is assumed to lie far enough across the membrane for bound ions to be affected by part of the potential difference across the membrane. Equations are derived for the general case where the blocking ion enters the channel from either side of the membrane. For H+ ion blockage, a simpler model, in which H+ enters the channel only from the bathing medium, is found to be sufficient. The dissociation constant of H+ ions from the channel site, 3.9 x 10-6 M (pKa 5.4), is like that of a carboxylic acid. From the voltage dependence of the block, this acid site is about one-quarter of the way across the membrane potential from the outside. In addition to blocking as described by the model, hydrogen ions also shift the responses of sodium channel "gates" to voltage, probably by altering the surface potential of the nerve. Evidence for voltage-dependent blockage by calcium ions is also presented.

Hyperlipidemia in Coronary Heart Disease II. GENETIC ANALYSIS OF LIPID LEVELS IN 176 FAMILIES AND DELINEATION OF A NEW INHERITED DISORDER, COMBINED HYPERLIPIDEMIA

Abstract: To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.

GENETIC CONTROL OF THE CELL DIVISION CYCLE IN YEAST: V. GENETIC ANALYSIS OF cdc MUTANTS

Abstract: One hundred and forty-eight temperature-sensitive cell division cycle (cdc) mutants of Saccharomyces cerevisiae have been isolated and characterized. Complementation studies ordered these recessive mutations into 32 groups and tetrad analysis revealed that each of these groups defines a single nuclear gene. Fourteen of these genes have been located on the yeast genetic map. Functionally related cistrons are not tightly clustered.Mutations in different cistrons frequently produce different cellular and nuclear morphologies in the mutant cells following incubation at the restrictive temperature, but all the mutations in the same cistron produce essentially the same morphology. The products of these genes appear, therefore, each to function individually in a discrete step of the cell cycle and they define collectively a large number of different steps.The mutants were examined by time-lapse photomicroscopy to determine the number of cell cycles completed at the restrictive temperature before arrest. For most mutants, cells early in the cell cycle at the time of the temperature shift (before the execution point) arrest in the first cell cycle while those later in the cycle (after the execution point) arrest in the second cell cycle. Execution points for allelic mutations that exhibit first or second cycle arrest are rather similar and appear to be cistron-specific. Other mutants traverse several cycles before arrest, and its suggested that the latter type of response may reveal gene products that are temperature-sensitive for synthesis, whereas the former may be temperature-sensitive for function.The gene products that are defined by the cdc cistrons are essential for the completion of the cell cycle in haploids of a and alpha mating type and in a/alpha diploid cells. The same genes, therefore, control the cell cycle in each of these stages of the life cycle.

General Method for the Isolation of Plasmid Deoxyribonucleic Acid

Abstract: Plasmid deoxyribonucleic acid (DNA) ranging from 5 × 106 to 65 × 106 daltons may be isolated from chromosomal DNA by the preferential precipitation of the higher-molecular-weight chromosomal DNA in the presence of sodium lauryl sulfate and a high concentration of NaCl.

The multiplier method of Hestenes and Powell applied to convex programming

Abstract: For nonlinear programming problems with equality constraints, Hestenes and Powell have independently proposed a dual method of solution in which squares of the constraint functions are added as penalties to the Lagrangian, and a certain simple rule is used for updating the Lagrange multipliers after each cycle. Powell has essentially shown that the rate of convergence is linear if one starts with a sufficiently high penalty factor and sufficiently near to a local solution satisfying the usual second-order sufficient conditions for optimality. This paper furnishes the corresponding method for inequality-constrained problems. Global convergence to an optimal solution is established in the convex case for an arbitrary penalty factor and without the requirement that an exact minimum be calculated at each cycle. Furthermore, the Lagrange multipliers are shown to converge, even though the optimal multipliers may not be unique.

The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine

Abstract: The inhibition of sodium currents by quaternary derivatives of lidocaine was studied in single myelinated nerve fibers. Membrane currents were diminished little by external quaternary lidocaine (QX). QX present in the axoplasm (<0.5 mM) inhibited sodium currents by more than 90%. Inhibition occurred as the sum of a constant, tonic phase and a variable, voltage-sensitive phase. The voltage-sensitive inhibition was favored by the application of membrane potential patterns which produce large depolarizations when sodium channels are open. Voltage-sensitive inhibition could be reversed by small depolarizations which opened sodium channels. One explanation of this observation is that QX molecules enter open sodium channels from the axoplasmic side and bind within the channels. The voltage dependence of the inhibition by QX suggests that the drug binds at a site which is about halfway down the electrical gradient from inside to outside of the sodium channel.

Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction

Abstract: Plasma cholesterol and triglyceride levels were measured after an overnight fast in 500 consecutively studied 3-mo survivors of myocardial infarction. Virtually all patients under 60 yr of age (95% ascertainment) and a randomly chosen group of older survivors admitted to 13 Seattle hospitals during an 11 mo period were included. A comparison of their lipid values with those of 950 controls demonstrated that 31% had hyperlipidemia. These lipid abnormalities were most commonly found in males under 40 yr of age (60% frequency) and in females under 50 yr of age (60% frequency). Elevation in triglyceride levels with (7.8%) or without (15.6%) an associated elevation in cholesterol levels was three times more common in survivors than a high cholesterol level alone (7.6%). These results raise the possibility that hypertriglyceridemia may be as an important a risk factor for coronary atherosclerosis as hypercholesterolemia. The identification of hyperlipidemic survivors of myocardial infarction provided a unique source of probands for family studies designed to disclose the genetic origin of hyperlipidemia in coronary heart disease.

Loss of control drinking in alcoholics: an experimental analogue

Abstract: W this landmark article was published in 1973, the domi­ nant model of alcoholism considered it a dispositional dis­ ease, the cardinal symptom of which is inevitable loss of control whenever alcohol is consumed. The reasons for this loss of con­ trol over drinking were generally assumed to be physiological, an automatic and irreversible reaction to the chemical ethanol (pure alcohol). A few controversial voices in the alcohol field, including Jellinek (as expressed in his book The Disease Concept of Alcoholism, 1960), had questioned the scientific accuracy of the disease model as a universal description of alcoholism. Nevertheless, it was widely believed that the essence of alcoholism was a biomedical abnor­ mality, inexorably rooted in the alco­ holic’s physical constitution. This innovative experiment by Marlatt and his colleagues put this assumption about alcoholism to the test by studying whether behavior changes resulted from the actual presence of alcohol or from the be­ lief that alcohol was present. The au­ thors introduced two novel research methods in this study, both of which inspired many subsequent studies. The first of these was the taste­rating task, in which subjects, made up of both alcoholics and social drinkers, were asked to taste and compare three ostensibly different beverages by rating them on a variety of de­ scriptive adjectives such as “sweet” and “strong.” The actual purpose of the task was to study the amount and manner of drinking the subjects did without making them self­conscious that their drinking was being moni­ tored. Later research has shown that this clever procedure does, in fact, mirror a person’s real­life drinking habits. It also is clear from two dec­ ades of subsequent studies that this unobtrusive measure is useful in gauging how a person’s drinking is affected by social and environ­ mental factors. The second innovative method in­ troduced in this study was the bal­ anced placebo design, which was made up of four groups of both alco­ holics and social drinkers: Subjects in two groups were told that they were drinking alcohol, and subjects in two groups were informed that there was no alcohol in the beverage. Under these conditions, one­half of the subjects received alcohol and one­half did not. Marlatt devised an effective method to disguise the presence of alcohol so that the subjects could be convinced they were drink­ ing alcohol when they were not (placebo group) or could be given alcohol without their being aware of it (balanced placebo group). This study’s central finding was that the subject’s belief that he was drinking alcohol, rather than its actual presence, deter­ mined the amount he consumed on the taste­rating task. This ef­ fect was found for both alcoholics and social drinkers, although the difference was greater for alcoholics. As a result of Marlatt and colleagues’ demonstration, the balanced placebo design be­ came a common research tool in the alcohol field. Dozens of subsequent studies have shown that it is the subject’s expectation

Organization of neurons in the visual cortex, area 17, of the monkey (Macaca mulatta).

Abstract: A study of neuron morphology in Golgi Rapid and Kopsch preparations of area 17 of the monkey has shown three basic cell groups— pyramidal neurons, stellate neurons with spinous dendrites and stellate neurons with spine-free or sparsely spined dendrites. These three neuron groups show different distributions in depth from pia to white matter and differ in their relationship to zones of concentrated termination of geniculo-cortical axons. The neuron type most closely related to the laminae receiving a heavy geniculo-cortical projection is the spinous stellate cell. This cell type is restricted to lamina IV. Included in this zone is the broadest band of geniculo-cortical axon projection (lamina IVC), the horizontal fiber band (lamina IVB) comprising the major portion of the stria of Gennari (receiving little or no thalamic projection) and the narrow band of thalamo-cortical fiber termination which occurs superficial to the stria of Gennari (lamina IVA). Pyramidal neuron cell bodies are almost totally excluded from lamina IVC and the apical dendrites of lower pyramidal neurons bear many fewer spines in lamina IVC than in laminae V and VI. The basal dendrites of upper pyramidal cells spread superficial and deep to lamina IVA rather than within it. Spine-free stellate neurons occur at all cortical levels and sparselyspined varieties have not been impregnated in lamina IV, but occur in the other laminae. Three groups of presumed thalamo-cortical axons have been identified, two of which resemble each other in morphology (having long collaterals which appear to terminate by means of spine-like projections of the axonal surface) but not in distribution. One group of these axons bearing spine-like projections distributes in laminae IVC (principally in the deeper half, IVCβ) and IVA; the other is restricted in distribution to the upper half of lamina IVC (IVCα). The third group of thalamo-cortical axons distributes to lamina I and appears to lack the spine-like projections shown by the other two axon groups.

The Metabolic Role of Lecithin: Cholesterol Acyltransferase: Perspectives from Pathology

Abstract: Publisher Summary This chapter discusses the metabolic role of enzyme lecithin called cholesterol acyltransferase (LCAT). The role of the LCAT reaction is to prevent unesterified cholesterol, derived mainly from the surfaces of chylomicrons and very low density lipoproteins, from accumulating in the plasma. This is successfully accomplished only when the LCAT reaction balances the mechanisms that increase plasma unesterified cholesterol. A balance does not occur in familial LCAT deficiency because the enzyme is absent. It does not occur in cholesterol-fed guinea pigs because unusually large amounts of dietary unesterified cholesterol enter the plasma through inadequate control in either the intestine or the liver. It does not occur in cholestasis because phospholipid bilayers are formed and promote the accumulation of unesterified cholesterol in plasma through increased hepatic biosynthesis. Unesterified cholesterol becomes associated with the surfaces of newly formed lipoproteins by physical equilibration within the cells of the intestinal mucosa and the liver. The function of the LCAT reaction is to transport unesterified cholesterol synthesized in peripheral tissues to the liver.

Ecology of Vibrio parahaemolyticus in Chesapeake Bay

Abstract: A study of the ecology of Vibrio parahaemolyticus and related vibrios in the Rhode River area of Chesapeake Bay was carried out over the period December 1970 through August 1971. The incidence of V. parahaemolyticus and related vibrios was found to be correlated with water temperature. The vibrios could not be detected in the water column during the winter months, although they were present in sediment. From late spring to early summer, when water temperatures were 14 ± 1 C, vibrios over-wintering in sediment were released from the bottom communities and attached to zooplankton, proliferating as the temperature rose. The number of vibrios in and on plankton was reflected in the water column bacterial population densities at water temperatures of ca. 19 C. Thus, temperature of the water column in the range of 14 to 19 C was found to be critical in the annual cycle of the vibrios. Interaction between sediment, water, and zooplankton was found to be essential in the natural estuarine ecosystem. Bacterial counts of zooplankton were found to be temperature dependent. The bacterial population associated with zooplankton was found to be predominantly on external surfaces and was specific, differing from that of the sediment. Vibrio spp. and related organisms comprised the total bacterial population associated with zooplankton in summer months. The ecological role of Vibrio spp., including V. parahaemolyticus, was found to be significant, with respect to their property of chitin digestion and in relation to the population dynamics of zooplankton in Chesapeake Bay.

Species Introduction in a Tropical Lake: A newly introduced piscivore can produce population changes in a wide range of trophic levels.

Abstract: Probably in early 1967, a piscivore from South America, Cichla ocellaris, was introduced to Gatun Lake in the Panama Canal Zone. As this predator population spread through the lake, the initial effect was dramatic reductions in almost all secondary consumers. These species reductions produced, in turn, second- and third-order changes at other trophic levels of the ecosystem. The resulting changes in the lake community can be seen best by examining the general Gatun Lake food web. The decrease in numbers of the important planktivore Melaniris has resulted in changes within the zooplankton community, as illustrated by the cladoceran Ceriodaphnia. The tertiary-consumer populations, such as tarpon, black terns, kingfishers, and herons, formerly dependent on small fishes for food, appear less frequently in the Cichla areas of the lake. There has also been, possibly, a resurgence of the local mosquito populations (which are malaria vectors), caused by the reduction in the populations of insect-eating fishes. Even the primary producers may be affected by this introduction. Although at present the Gatun Lake ecosystem is undergoing rapid changes, we anticipate an eventual return to some form of equilibrium. However, it will be some time before we can evaluate the permanence or transience of the many changes produced in the trophic levels by the introduction of a single, top-level predator to this lake system.

A dual approach to solving nonlinear programming problems by unconstrained optimization

Abstract: Several recent algorithms for solving nonlinear programming problems with equality constraints have made use of an augmented “penalty” Lagrangian function, where terms involving squares of the constraint functions are added to the ordinary Lagrangian. In this paper, the corresponding penalty Lagrangian for problems with inequality constraints is described, and its relationship with the theory of duality is examined. In the convex case, the modified dual problem consists of maximizing a differentiable concave function (indirectly defined) subject to no constraints at all. It is shown that any maximizing sequence for the dual can be made to yield, in a general way, an asymptotically minimizing sequence for the primal which typically converges at least as rapidly.

Acyclic colorings of planar graphs

Abstract: A coloring of the vertices of a graph byk colors is called acyclic provided that no circuit is bichromatic. We prove that every planar graph has an acyclic coloring with nine colors, and conjecture that five colors are sufficient. Other results on related types of colorings are also obtained; some of them generalize known facts about “point-arboricity”.

Potassium Channels in Myelinated Nerve Selective permeability to small cations

Abstract: The permeability of K channels to various cations is studied in myelinated nerve. Ionic currents under voltage clamp are measured in Ringer solution containing tetrodotoxin and a high concentration of the test ion. Reversal potentials for current in K channels are determined and used with the Goldman-Hodgkin-Katz equation to calculate relative permeabilities. The ratios PTl:PK:PRb:PNHNH4 are 2.3:1.00:0.92:0.13. No other ions are found to be measurably permeant including Li+, Na+, Cs+, methylamine, guanidine, hydrazine, or hydroxylamine. The ratio PNa/PK is less than 0.01. Potassium conductance is depressed at pH values below 5.0. Leakage conductance is higher in K, Rb, Cs, NH4, and Tl Ringer than in Na Ringer, but the selectivity sequence probably is not the same as for K channels. The hypothesis is offered that the narrowest part of the K channel is a circle of oxygen atoms about 3 A in diameter with low electrostatic field strength.

The Structure and Dynamics of Horizontal Roll Vortices in the Planetary Boundary Layer

Abstract: The wind and temperature fields of the Planetary boundary layer (PBL) are investigated during periods in which horizontal roll vortices are present. Measurements from a 444 m tower and from inertially-stabilized aircraft indicate the rolls are maintained primarily by 1) production of energy from the cross-roll component of the mean PBL wind spiral (inflectional instability and 2) buoyancy. Complicating a simple picture of two-dimensional rolls are other kilometer-scale eddies whose energy exchanges with the tolls may be important. The importance of inflectional instability is indicated by the similarity of roll structure to that predicted by models based on the formation of the rolls as a result of instability in the cross-wind (V component of the Ekman spiral. Rolls observed are generally oriented from 10° to 20° to the left of the wind at inversion base, with maximum roll vertical velocity at 0.33zi(where zi is inversion height) and maximum lateral velocity at 0.07zi Atmospheric roll magnitude ...

Anomalous Behavior of Synchronizer and Arbiter Circuits

Abstract: Observations are shown of oscillatory and metastable behavior of flip-flops in response to logically undefined input conditions such as those that occur in synchronizers and arbiters. Significant systems failures have resulted from this fundamentally inescapable problem that is generally not appreciated by system designers and users.

Absorption coefficient of atmospheric aerosol: a method for measurement.

Abstract: Recent models predict that the effect of atmospheric aerosol particles on global temperature depends in part on b(abs,)or on n(2), where b(abs) is the aerosol absorption coefficient, and n(2) is the imaginary part of the aerosol refractive index for radiation in visible wavelengths Satisfactory techniques for measuring b(abs) have yet to be developed A method for measurement of b(abs) is described and discussed The apparatus uses a piece of opal glass to integrate light scattered by particles collected on Nuclepore filters It is quite mobile, inexpensive, and can be calibrated Analysis of the errors inherent in the measurement shows it is accurate to well within an order of magnitude for particles of radius larger than 01 microm

On catching on to idiomatic expressions.

Abstract: These experiments concern the comprehension of idiomatic expressions. The hypothesis was that there are distinct idiomatic and literal modes of processing sentences. In two experiments, 414 undergraduates read a series of sentences containing either literal or idiomatic ambiguities and then a test which had both a literal and an idiomatic meaning. Ss recorded, which meaning they perceived first. Taken together, the experiments indicate that inducing a set to perceive idioms can increase the proportion of people seeing the idiomatic meaning of test sentence first and a set to perceive literal meanings can reduce this proportion compared to a no-set baseline. Since the procedures to induce set did not involve grammatical or semantic information relevant to comprehension of the test sentence, these results suggest the existence of distinct literal and idiomatic processing strategies.