In recent years, a variety of low molecular weight antibiotics have been isolated from diverse animal species. These agents, which include peptides, lipids, and alkaloids, exhibit antibiotic activity against environmental microbes and are thought to play a role in innate immunity. We report here the discovery of a broad-spectrum steroidal antibiotic isolated from tissues of the dogfish shark Squalus acanthias. This water-soluble antibiotic, which we have named squalamine, exhibits potent bactericidal activity against both Gram-negative and Gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. The chemical structure of the antibiotic 313-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane}-7a,24'-dihydroxy-Sacholestane 24-sulfate has been determined by fast atom bombardment mass spectroscopy and NMR. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. The discovery of squalamine in the shark implicates a steroid as a potential host-defense agent in vertebrates and provides insights into the chemical design of a family of broad-spectrum antibiotics.Animals must defend themselves against environmental microbes if they are to survive. Multiple mechanisms of host defense against microbes have been described such as the array of humoral and cellular responses of the classical vertebrate immune system and less-specific physical and chemical barriers. Over the past several years, an increasing number of low molecular weight antibiotic substances, believed to play a role in defense against environmental microbes, have been isolated from diverse species of animals. These molecules include peptides (1-3), lipids (4, 5), and alkaloids (6-8).In the course of our studies exploring the diversity of antibiotics from animal sources, we have surveyed tissues from a number of animal species (9, 10). We focused our search for antibiotic substances on the gastrointestinal tract of various animals after the recent discovery of peptide antibiotics in the gut of frogs (11), pigs (12, 13), mice (14), and humans (34). In the course of our survey, we discovered that stomach extracts of the shark Squalus acanthias exhibited potent antimicrobial activity, prompting efforts to purify and identify the responsible molecule.In this report we describe the isolation, structural determination, and characterization of a water-soluble cationic steroid from the shark that exhibits potent antimicrobial activity against fungi, protozoa, and both Gram-negative and Gram-positive bacteria. This molecule is shown to be an unusual adduct of spermidine with an anionic bile salt intermediate that, to our knowledge, is without precedent in vertebrates. We have named the aminosterol "squalamine," derived from the genus Squalus and its chemical structure as an amine. MATERIALS AND METHODSPurification of Squlamine. Squalus acanthias sharks were captured off the New England coast. The shark stomach tissue (400 g) was frozen immediately after dissectio...

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The isolated rectal gland of Squalus acanthias was stimulated to secrete chloride against an electrical and a chemical gradient when perfused in vitro by theophylline and/or dibutyryl cyclic AMP. Chloride secretion was depressed by ouabain which inhibits Na-K-ATPase. Thiocyanate and furosemide also inhibited chloride secretion but ethoxzolamide, a carbonic anhydrase inhibitor, did not. Chloride transport was highly dependent on sodium concentration in the perfusate. The intracellular concentration of chloride averaged 70-80 meq/liter in intact glands, exceeding the level expected at electrochemical equilibrium and suggesting active transport of chloride into the cell. These features suggest a tentative hypothesis for chloride secretion by the rectal gland in which the uphill transport of chloride into the cytoplasm is coupled through a membrane carrier to the downhill movement of sodium along its electrochemical gradient. The latter is maintained by the Na-K-ATPase pump while chloride is extruded into the duct by electrical forces.

Purpose – The purpose of this paper is to summarize the progress in grey system research during 2000-2015, so as to present some important new concepts, models, methods and a new framework of grey system theory. Design/methodology/approach – The new thinking, new models and new methods of grey system theory and their applications are presented in this paper. It includes algorithm rules of grey numbers based on the “kernel” and the degree of greyness of grey numbers, the concept of general grey numbers, the synthesis axiom of degree of greyness of grey numbers and their operations; the general form of buffer operators of grey sequence operators; the four basic models of grey model GM(1,1), such as even GM, original difference GM, even difference GM, discrete GM and the suitable sequence type of each basic model, and suitable range of most used grey forecasting models; the similarity degree of grey incidences, the closeness degree of grey incidences and the three-dimensional absolute degree of grey incidence of grey incidence analysis models; the grey cluster model based on center-point and end-point mixed triangular whitenization functions; the multi-attribute intelligent grey target decision model, the two stages decision model with grey synthetic measure of grey decision models; grey game models, grey input-output models of grey combined models; and the problems of robust stability for grey stochastic time-delay systems of neutral type, distributed-delay type and neutral distributed-delay type of grey control, etc. And the new framework of grey system theory is given as well. Findings – The problems which remain for further studying are discussed at the end of each section. The reader could know the general picture of research and developing trend of grey system theory from this paper. Practical implications – A lot of successful practical applications of the new models to solve various problems have been found in many different areas of natural science, social science and engineering, including spaceflight, civil aviation, information, metallurgy, machinery, petroleum, chemical industry, electrical power, electronics, light industries, energy resources, transportation, medicine, health, agriculture, forestry, geography, hydrology, seismology, meteorology, environment protection, architecture, behavioral science, management science, law, education, military science, etc. These practical applications have brought forward definite and noticeable social and economic benefits. It demonstrates a wide range of applicability of grey system theory, especially in the situation where the available information is incomplete and the collected data are inaccurate. Originality/value – The reader is given a general picture of grey systems theory as a new model system and a new framework for studying problems where partial information is known; especially for uncertain systems with few data points and poor information. The problems remaining for further studying are identified at the end of each section.

PurposeThe purpose of this paper is to introduce the elementary concepts and fundamental principles of grey systems and the main components of grey systems theory. Also to discuss the astonishing progress that grey systems theory has made in the world of learning and its wide‐ranging applications in the entire spectrum of science.Design/methodology/approachThe characteristics of unascertained systems including incomplete information and inaccuracies in data are analysed and four uncertain theories: probability statistics, fuzzy mathematics, grey system and rough set theory are compared. The scientific principle of simplicity and how precise models suffer from inaccuracies are also shown.FindingsThe four uncertain theories, probability statistics, fuzzy mathematics, grey system and rough set theory are examined with different research objects, different basic sets, different methods and procedures, different data requirements, different emphasis, different objectives and different characteristics.Practical implicationsThe scientific principle of simplicity and how precise models suffer from inaccuracies are shown. So, precise models are not necessarily an effective means to deal with complex matters, especially in the case that the available information is incomplete and the collected data inaccurate.Originality/valueThe elementary concepts and fundamental principles of grey systems and the main components of grey systems theory are introduced briefly. The reader is given a general picture of grey systems theory as a new method for studying problems where partial information is known, partial information is unknown; especially for uncertain systems with few data points and poor information.

A B S.T R A C T The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results

PurposeThe purpose of this paper is to solve the problems existing in traditional grey incidence models and advance several new grey incidence models based on visual angle of similarity and nearness.Design/methodology/approachBased on the definition of traditional grey incidence models, two novel grey incidence models, grey similar incidence model and grey close incidence model, are studied in this paper. The interrelations and influence can be measured by the new models with different visual angle of similarity and/or nearness, respectively. The grey similar incidence model is used mainly to measure the similitude degree of the geometric patterns of sequence curves. The grey close incidence model is used mainly to measure the nearness of the sequence curves in space. The properties of the new models are discussed. It is proved that the proposed models are simplified methods to calculate the similitude degree and the close degree of grey incidence models.FindingsThe results show that the two novel grey incidence models satisfy the grey incidence axiom properly. It is useful to calculate the similitude degree and the close degree of two different sequences, and the process of calculating is easier than with traditional grey incidence models.Practical implicationsThe method exposed in the paper can be used to calculate every two sequences. The similitude degree and the close degree of two different sequences can be given out. The method can also be used to rank sequences of more than two.Originality/valueThe paper succeeds in constructing two novel grey incidence models. The properties of novel model are studied and it is undoubtedly a new development in grey systems theory.

We evaluated demeclocycline and lithium therapy in 10 patients with the syndrome of inappropriate secretion of antidiuretic hormone. Despite severe water restriction, all patients had hyponatremia (mean +/- S.E.M. serum sodium of 122 +/- 1.1 meq per liter) and elevated urine osmolality (744 +/- 59 mOsm per kilogram) before treatment. Demeclocycline (600 to 1200 mg daily) restored serum sodium concentration to 139 +/- 1.1 meq per liter within five to 14 days, permitting unrestricted water intake in all patients. In three patients given lithium carbonate (900 mg daily) the serum sodium concentration, urine osmolality and urine volume were unchanged; since two patients had adverse central-nervous-system symptoms during lithium therapy, further study of this agent was abandoned. A patient with an unusual 22-year history of the syndrome was unresponsive to lithium, whereas long-term treatment with demeclocyline was markedly effective. Demeclocycline is superior to lithium in the treatment of the syndrome and may obviate the need for severe water restriction.