Characterization Of The Active Site Of Urokinase With A Series Of Potent Inhibitory Amidines

1981 ◽  
Author(s):  
J D Geratz ◽  
S R Shaver ◽  
R R Tidwell
Keyword(s):  
Active Site ◽  
Factor Xa ◽  
Selective Inhibition ◽  
The Other ◽  
Plasminogen Activation ◽  
Steric Factors ◽  
The Difference ◽  
The One ◽  
Striking Contrast

Twenty amidine-substituted indole-like heterocycles were synthesized and examined for their blocking effect against human urokinase and a number of related arginine- or lysine- directed proteases. Kinetic analyses were carried out with the help of peptide anilide substrates and revealed a reversible competitive inhibitory pattern with each compound. The Ki values were therefore interpreted to reflect binding conditions at the active site of the enzymes.A highly potent inhibitor of urokinase was discovered in 5-amidino-l-(4-amidinobenzyl)indole which proved to be 18 times more effective on a molar basis than p-aminobenzamidine and 150 times more effective than benzamidine. The Ki value at 37°C and pH 8.3 was determined as 3.2 × 10-6 M. In striking contrast to the findings with the other proteases studied, urokinase was very sensitive to inhibition by 6-amidinoindoline (Ki 1.8 × 10-5 M), yet was much less susceptible to inhibition by the fully unsaturated analog 6-amidinoindole. Steric factors resulting from the difference in planarity between the two compounds are held responsible for this observation. In plasminogen activation assays the antiurokinase effect of the heterocycles mirrored their potency in the assays employing the synthetic urokinase substrate.The significant differences in the inhibitory activities of amidines against urokinase, on the one hand, and plasmin, thrombin and factor Xa, on the other hand, will be useful for experiments where selective inhibition of plasminogen activation is to be achieved. The compounds will also be of help in characterizing other tissue activators with respect to urokinase.

Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

1986 ◽  
Vol 56 (03) ◽  
pp. 349-352 ◽  
Author(s):  
A Tripodi ◽  
A Krachmalnicoff ◽  
P M Mannucci
Keyword(s):  
Venous Thromboembolism ◽  
Active Site ◽  
Inhibitory Activity ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Molecular Defect ◽  
Affinity Adsorption ◽  
Italian Family ◽  
Crossed Immunoelectrophoresis

SummaryFour members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

scholarly journals EXPERIMENTAL EPIDEMIOLOGY OF TUBERCULOSIS

1930 ◽  
Vol 51 (5) ◽  
pp. 769-776 ◽  
Author(s):  
Max B. Lurie
Keyword(s):  
Guinea Pigs ◽  
Wire Mesh ◽  
The Other ◽  
Tuberculous Infection ◽  
Source Of Infection ◽  
Natural Modes ◽  
The Difference ◽  
The One ◽  
Portal Of Entry ◽  
Human Autopsy Material

Under conditions closely simulating the natural modes of tuberculous infection in man normal guinea pigs have acquired tuberculosis by being exposed under two degrees of crowding to tuberculous cage mates in ordinary cages, where the food became soiled with excreta, bearing tubercle bacilli, and in special cages, with wire-mesh floors, where this source of infection was almost entirely eliminated. Guinea pigs were also exposed in the same room but not in the same cage with tuberculous animals. It was found that the relative tuberculous involvement of the mesenteric and tracheobronchial nodes showed a gradation of change from an almost completely alimentary infection to a completely respiratory infection. The disease involved the mesenteric nodes predominantly in the crowded ordinary cages, with much less or no affection of the tracheobronchial nodes. It was similarly, but less markedly, enteric in origin in the less crowded ordinary cages, the mesenteric nodes again being larger than the tracheobronchial nodes, but the difference in size was not so great. In the more crowded special cages the relative affection of these two groups of nodes alternated, so that in some the mesenteric, in some the tracheobronchial nodes were more extensively tuberculous. A disease characterized by less or no affection of the mesenteric nodes and by extensive lesions of the tracheobronchial nodes was seen in the less crowded special cages. Finally there was a massive tuberculosis of the tracheobronchial nodes with usually no affection of the mesenteric nodes in the frankly air-borne tuberculosis acquired by guinea pigs exposed in the same room but not to tuberculous cage mates. This gradation in the rô1e played by the enteric and respiratory routes of infection, as first the one and then the other becomes the more frequent channel of entrance for tuberculosis, would indicate that the penetration of tubercle bacilli by the one portal of entry inhibits the engrafting of tuberculosis in the tissues by way of the other portal of entry. It is apparent that in the special cages the opportunities for inhaling tubercle bacilli are at most equal to if not much less than in the ordinary cages; for in the latter dust from the bedding, laden with tubercle bacilli, is stirred up almost constantly by the animals, whereas in the special cages there is no bedding at all, and therefore, presumably, no more tubercle bacilli in the air than may occur in any part of the room. Nevertheless the route of infection was predominantly the respiratory tract in the special cages, especially in the less crowded, apparently because the enteric route had been largely eliminated. The greater predominance of the respiratory route amongst guinea pigs that acquired tuberculosis in the less crowded ordinary cages as compared to the lesser significance of this route in the more crowded ordinary cages would point in the same direction. These observations are in harmony with our knowledge that tuberculosis once implanted in an organism confers a certain degree of immunity to the disease. It is noteworthy that in a study of human autopsy material Opie (3) has found that when healed lesions are present in the mesentery focal tuberculosis in the lungs is seldom found, and that when first infection occurs by way of the lungs it tends to prevent the engrafting of the disease by way of the intestinal tract.

A semi-hybrid model for malaria with limited superinfection

1998 ◽  
Vol 30 (04) ◽  
pp. 1027-1057 ◽  
Author(s):  
Philippe Picard
Keyword(s):  
Stochastic Model ◽  
Population Size ◽  
Hybrid Model ◽  
Human Population ◽  
Threshold Level ◽  
The Other ◽  
The Difference ◽  
The One

Modelling malaria with consistency necessitates the introduction of at least two families of interconnected processes. Even in a Markovian context the simplest fully stochastic model is intractable and is usually transformed into a hybrid model, by supposing that these two families are stochastically independent and linked only through two deterministic connections. A model closer to the fully stochastic model is presented here, where one of the two families is subordinated to the other and just a unique deterministic connection is required. For this model a threshold theorem can be proved but the threshold level is not the one obtained in a hybrid model. The difference disappears only when the human population size approaches infinity.

scholarly journals XXIII.—On the Disruptive Discharge of Electricity: An Experimental Thesis for the Degree of Doctor of Science, Department A

1878 ◽  
Vol 28 (2) ◽  
pp. 633-671 ◽  
Author(s):  
Alexander Macfarlane
Keyword(s):  
Copper Wire ◽  
Late Summer ◽  
The Other ◽  
Straight Line ◽  
Summer Session ◽  
The Difference ◽  
A Chain ◽  
The One ◽  
Metallic Parts ◽  
The University

The experiments to which I shall refer were carried out in the physical laboratory of the University during the late summer session. I was ably assisted in conducting the experiments by three students of the laboratory,—Messrs H. A. Salvesen, G. M. Connor, and D. E. Stewart. The method which was used of measuring the difference of potential required to produce a disruptive discharge of electricity under given conditions, is that described in a paper communicated to the Royal Society of Edinburgh in 1876 in the names of Mr J. A. Paton, M. A., and myself, and was suggested to me by Professor Tait as a means of attacking the experimental problems mentioned below.The above sketch which I took of the apparatus in situ may facilitate tha description of the method. The receiver of an air-pump, having a rod capable of being moved air-tight up and down through the neck, was attached to one of the conductors of a Holtz machine in such a manner that the conductor of the machine and the rod formed one conducting system. Projecting from the bottom of the receiver was a short metallic rod, forming one conductor with the metallic parts of the air-pump, and by means of a chain with the uninsulated conductor of the Holtz machine. Brass balls and discs of various sizes were made to order, capable of being screwed on to the ends of the rods. On the table, and at a distance of about six feet from the receiver, was a stand supporting two insulated brass balls, the one fixed, the other having one degree of freedom, viz., of moving in a straight line in the plane of the table. The fixed insulated ball A was made one conductor with the insulated conductor of the Holtz and the rod of the receiver, by means of a copper wire insulated with gutta percha, having one end stuck firmly into a hole in the collar of the receiver, and having the other fitted in between the glass stem and the hollow in the ball, by which it fitted on to the stem tightly. A thin wire similarly fitted in between the ball B and its insulating stem connected the ball with the insulated half ring of a divided ring reflecting electrometer.

Scenarios as Tools of the Scientific Imagination: The Case of Climate Projections

2021 ◽  
Vol 29 (1) ◽  
pp. 36-61
Author(s):  
Michael Poznic ◽  
Rafaela Hillerbrand
Keyword(s):  
Scientific Community ◽  
Climate Science ◽  
The Other ◽  
Climate Projections ◽  
Public Realm ◽  
The Public ◽  
Other Hand ◽  
The Difference ◽  
The One ◽  
Scientific Imagination

Climatologists have recently introduced a distinction between projections as scenario-based model results on the one hand and predictions on the other hand. The interpretation and usage of both terms is, however, not univocal. It is stated that the ambiguities of the interpretations may cause problems in the communication of climate science within the scientific community and to the public realm. This paper suggests an account of scenarios as props in games of make-belive. With this account, we explain the difference between projections that should be make-believed and other model results that should be believed.

The Maximum Claims of Gauthier's Bargainers: Are the Fixed Social Inequalities Acceptable?

Dialogue ◽  
1982 ◽  
Vol 21 (3) ◽  
pp. 411-429
Author(s):  
David Braybrooke
Keyword(s):  
Social Contract ◽  
Social Inequalities ◽  
Social Contract Theory ◽  
The Other ◽  
Relative Advantage ◽  
Central Feature ◽  
Maximum Utility ◽  
The Difference ◽  
The One ◽  
Principle Of Maximum

A central feature of David Gauthier's impressively searching version of social contract theory is the principle of maximin relative advantage. Given certain assumptions—more than he originally thought—this principle may be described as calling for maximum equal advantage, which is easier to talk about; and I shall refer to the principle under this description. Maximum equal relative advantage is equivalent to minimum equal relative concession; hence the principle of maximum equal relative advantage has a twin and mirror, the principle of minimum equal relative concession. Relative advantage and relative concession are ratios with the same denominator, the difference for a given agent between the maximum utility (umax) that she might get from the societyt o be contracted for and the minimum utility (umin) that would give her an incentive to cooperate in establishing the society and in keeping it up. The numerator for the one ratio—relative advantage—is the difference between the utility that she is actually going to gain from society (ua) and her minimum cooperative utility (umin). The numerator for the other ratio—relative concession—is the difference between her maximum utility (umax) and the utility that she is going to get (ua), in other words, the amount of utility that she foregoes in not getting her maximum.

scholarly journals Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

2018 ◽  
Vol 61 (22) ◽  
pp. 10000-10016 ◽  
Author(s):  
Martin Marek ◽  
Tajith B. Shaik ◽  
Tino Heimburg ◽  
Alokta Chakrabarti ◽  
Julien Lancelot ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Selective Inhibition ◽  
Histone Deacetylase 8

scholarly journals The principal magnetic susceptibilities of neodymium sulphate octahydrate at low temperatures

1939 ◽  
Vol 170 (941) ◽  
pp. 266-271 ◽  
Keyword(s):  
Low Temperatures ◽  
Room Temperature ◽  
Energy Levels ◽  
Constant Factor ◽  
The Other ◽  
Crystalline Field ◽  
Cubic Symmetry ◽  
The Subject ◽  
The Difference ◽  
The One

The magnetic and other related properties of neodymium sulphate have been the subject of numerous investigations in recent years, but there is still a remarkable conflict of evidence on all the essential points. The two available determinations of the susceptibility of the powdered salt at low temperatures, those of Gorter and de Haas (1931) from 290 to 14° K and of Selwood (1933) from 343 to 83° K both fit the expression X ( T + 45) = constant over the range of temperature common to both, but the constants are not the same and the susceptibilities at room temperature differ by 11%. The fact that the two sets of results can be converted the one into the other by multiplying throughout by a constant factor suggested that the difference in the observed susceptibilities was due to some error of calibration. It could, however, also be due to the different purity of the samples examined though the explanation of the occurrence of the constant factor is then by no means obvious. From their analysis of the absorption spectrum of crystals of neodymium sulphate octahydrate Spedding and others (1937) conclude that the crystalline field around the Nd+++ ion is predominantly cubic in character since they find three energy levels at 0, 77 and 260 cm. -1 .* Calculations of the susceptibility from these levels reproduce Selwood’s value at room temperature but give no agreement with the observations-at other temperatures. On the other hand, Penney and Schlapp (1932) have shown that Gorter and de Haas’s results fit well on the curve calculated for a crystalline field of cubic symmetry and such a strength that the resultant three levels lie at 0, 238 and 834 cm. -1 , an overall spacing almost three times as great as Spedding’s.

English as a Lingua Franca in the Expanding Circle

2013 ◽  
Author(s):  
Jennifer Jenkins
Keyword(s):  
Community Of Practice ◽  
Empirical Research ◽  
The Other ◽  
Speech Community ◽  
Lingua Franca ◽  
Expanding Circle ◽  
Contact Language ◽  
First Languages ◽  
The Difference ◽  
The One

This article discusses English in terms of its role as a contact language among expanding circle users of English from different first languages. It begins by observing both similarities between English as a Lingua Franca (ELF) and other lingua francas, and the difference in scale between them, with ELF involving a far higher number of people and first languages. The article goes on to explore empirical research into ELF, and its key findings: on the one hand, that certain “nonstandard” English forms are regularly preferred to “standard” (i.e. native) ones, and on the other, that ELF is far more affected by context and accommodation processes, and, therefore, far more diverse, than native Englishes. The notion of “community of practice,” it is argued, is, thus, more appropriate to ELF than that of “speech community.” The article concludes by considering three key areas of ELF research that need to be tackled.

Limit theorems and absorption problems for quantum radom walks in one dimension

2002 ◽  
Vol 2 (Special) ◽  
pp. 578-595
Author(s):  
N. Konno
Keyword(s):  
Random Walks ◽  
Limit Theorems ◽  
The Other ◽  
One Dimension ◽  
Unitary Matrices ◽  
Quantum Random Walks ◽  
One Dimensional ◽  
The Difference ◽  
The One

In this paper we consider limit theorems, symmetry of distribution, and absorption problems for two types of one-dimensional quantum random walks determined by $2 \times 2$ unitary matrices using our PQRS method. The one type was introduced by Gudder in 1988, and the other type was studied intensively by Ambainis et al. in 2001. The difference between both types of quantum random walks is also clarified.

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