Hoplonemertine worms—a new source of pyridine neurotoxins

Summary Two pyridine bases were isolated from the marine hoplonemertineAmphiporus angulatus (Fabricius) and identified by mass and PMR-spectroscopy as 2,3-bipyridyl and 3,2; 3,2; 4,3'-tetrapyridyl (Nemertelline). Nemertelline, the first tetrapyridyl natural product to be reported, shows a structural resemblance to the tobacco constituent nicotelline. The crustacean toxicity of 2,3-bipyridyl is very similar to that of nicotine, but its mammalian toxicity is negligible.We thank DoctorsN. Meinkoth andN. Riser for collecting specimens, Dr.F. Kuffner for providing the nicotelline sample, Dr.C. Westerman for recording initial PMR-spectra, and Dr.R. King for furnishing the computer simulation program and recording the high resolution mass spectra, and Mr.J. Babashak for use of the Kontes densitometer. This research was supported by an NIH-GRS grant and by the Veterans Administration (No. MRIS-9416).     

Proteases of Antarctic krill—a new system for effective enzymatic debridement of necrotic ulcerations

Summary The Antarctic krill (Euphausia superba) possesses an over-dimensioned digestive system, which is of vital importance for the survival of this euphaucean shrimp in the extreme marine environment. The isolated enzymes contain a well-balanced mixture of both endo- and exopeptidases, assuring fast and complete breakdown of proteinaceous material. These unique properties have now been shown to be extremely valuable for the effective removal of necrotic debris, fibrin or blood crusts in vitro. Therefore the krill enzymes should be considered as an important resource in the future management of necrotic wounds.     

‘Classical’ and ‘new’ diabetogens—comparison of their effects on isolated rat pancreatic islets in vitro

This study compares functional and morphological alterations caused by application of alloxan, streptozotocin, xanthine oxidase/hypoxanthine (generation of reactive oxygen species), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, liberation of nitric oxide) to isolated rat pancreatic islets in vitro. In perifusion experiments, membrane leakage—detected by non-stimulated insulin release—was found after application of all drugs, but showed a substance-specific time pattern. Twenty-four hours after application of the classical diabetogens (alloxan or streptozotocin), potassium chloride- and glucose-stimulated insulin secretion were markedly reduced, while a persistent reduction was observed neither after exposure to xanthine oxidase/hypoxanthine, nor to SNAP. Morphological analysis of the islets revealed that nearly all β-cells were destroyed following alloxan or streptozotocin treatment, while the majority of β-cells were configured regularly after application of xanthine oxidase/hypoxanthine or SNAP. Necrotic cells found after xanthine oxidase/hypoxanthine usually differed in morphology from those observed after application of the classical diabetogens. While the former cells were characterised by swollen nuclei, the latter had shrunken nuclei with irregular condensed chromatin. Apoptosis was found only following nitric oxide exposure. Due to these differences, it seems unlikely that alloxan, streptozotocin, xanthine oxidase/hypoxanthine, and nitric oxide have a common major feature in their toxic action. Received 16 September 1999; received after revision 15 November 1999; accepted 26 November 1999     

Ketoconazole — a new broad spectrum orally active antimycotic

Summary Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.This work was supported by the Instituut tot Aanmoediging van het Wetenschappelijk Onderzoek in Nijverheid en Landbouw.     

Dyslexia and specifically distorted drawings of the face—a new subgroup with prosopagnosia-like signs

Summary Identification of a subgroup (38%) of dyslexics (new syndrome?). These, against controls (5.5%), drew neolithic face configurations analogous to those visually experienced in prosop-agnosia. Essential symptoms of this subgroup are seen as result of specific early ways of processing visual data: lexical shapes (letters, words) and facial features, as if these were concrete entities, not abstract component parts. Thus, with letters, taken as entities, d=q, d=b, N=Z.This study was made possible by a visiting professorship at the University of Heidelberg, Department of Neurology. Thanks are due to its Director, Professor Dr.Heinz Gänshirt, as well as to DirectorSchmitt of the Heidelberger Schulamt and to Psychologist GretRuder-Trümpy for facilitating the collection of the drawings.     

The cucumber tendril — a new test organ for gibberellic acid

Résumé On peut se servir de tronçons de vrilles de concombre en voie de dévelopmentin vitro, pour déterminer d'après leurs réactions la présence d'acide gibberellique (GA). L'avantage de cette méthode réside dans le fait qu'on peut l'employer en la combinant avec la chromatographie sur papier et ainsi évaluer le GA dans l'extrait des plantes.     

α-Endosulfine, a new entity in the control of insulin secretion

ATP-dependent potassium (K_ATP) channels occupy a key position in the control of insulin release from the pancreatic β cell since they couple cell polarity to metabolism. These channels close when more ATP is produced via glucose metabolism. They are also controlled by sulfonylureas, a class of drugs used in type 2 diabetic patients for triggering insulin secretion from β cells that have lost part of their sensitivity to glucose. We have demonstrated the existence of endogenous counterparts to sulfonylureas which we have called ‘endosulfines.’ In this review, we describe the discovery, isolation, cloning, and biological features of the high-molecular-mass form, α-endosulfine, and discuss its possible role in the physiology of the β cell as well as in pathology. Received 1 February 1999; received after revision 26 March 1999; accepted 26 March 1999     

The peroxisomal protein import machinery – a case report of transient ubiquitination with a new flavor

The peroxisomal protein import machinery displays remarkable properties. Be it its capacity to accept already folded proteins as substrates, its complex architecture or its energetics, almost every aspect of this machinery seems unique. The list of unusual properties is still growing as shown by the recent finding that one of its central components, Pex5p, is transiently monoubiquitinated at a cysteine residue. However, the data gathered in recent years also suggest that the peroxisomal import machinery is not that exclusive and similarities with p97/Cdc48-mediated processes and with multisubunit RING-E3 ligases are starting to emerge. Here, we discuss these data trying to distill the principles by which this complex machinery operates. Received 16 July 2008; received after revision 25 August 2008; accepted 29 August 2008     

Goitrin — a nitrosatable constituent of plant foodstuffs

Summary N-nitrosamides are known as direct-acting carcinogens at the site of their formation; they do not need any metabolic activation in vivo. The conditions leading to their formation in the stomach, and also their genotoxicity, have been thoroughly studied with some model compounds^{1, 2}. Several reports link this type of compound to the induction of gastric cancer in human^{3, 4}. However, only limited data are presently available about possible precursors of N-nitrosamides in foods. In the present study we found that goitrin — a naturally occurring compound in cruciferous vegetables and rape—could be easily nitrosated by treatment with nitrite under stomach conditions, yielding with loss of sulfur the N-nitroso-oxazolidone4 (fig.). This product has a mutagenicity pattern and potency similar to that of N-nitroso-N-methyl-N-nitroguanidine (MNNG) in the Ames Salmonella/mammalian microsome test.     

Nicotianamine,the ‘normalizing factor’ for the auxotroph tomato mutantChloronerva; a representative of a new class of plant effectors

Summary The article surveys our knowledge of the normalizing factor, gained from its discovery a quarter of a century ago up to the present time, under the following headings: Discovery; Physiological properties; Isolation and characterization; Structure determination (Identity of the normalizing factor with nicotianamine); Chemical properties; Analysis; Synthesis; Occurrence and physiological role; Related compounds; Prospects.     

The folding process of hen lysozyme: a perspective from the ‘new view’

How a conformationally disordered polypeptide chain rapidly and efficiently achieves its well-defined native structure is still a major question in modern structural biology. Although much progress has been made towards rationalizing the principles of protein structure and dynamics, the mechanism of the folding process and the determinants of the final fold are not yet known in any detail. One protein for which folding has been studied in great detail by a combination of diverse techniques is hen lysozyme. In this article we review the present state of our knowledge of the folding process of this enzyme and focus in particular on recent experiments to probe some of its specific features. These results are then discussed in the context of the ‘new view’ of protein folding based on energy surfaces and land scapes. It is shown that a schematic energy surface for lysozyme folding, which is broadly consistent with our experimental data, begins to provide a unified model for protein folding through which experimental and theoretical ideas can be brought together.     

Pregnancy specificβ 1 — a product of the syncytiotrophoblast

Summary Pregnancy specific ₁ (PSG) has been identified in vitro in trophoblast cultures and in vivo, using transmission electron microscopy, in the syncytiotrophoblast, PSG may, like other pregnancy proteins, have immunosuppressive properties.This study was supported by a grant from the Medical Research Council. We thank Dr.D. R. Abramovich for making available the first trimester placentae and MissWanda Emslie for help in the tissue culture studies.     

A new synthesis ofβ-fluoroaspartic acid

Summary -Fluoroaspartic acid, a new amino acid, was synthesized by a diazotization of diaminosuccinic acid in liquid hydrogen fluoride.Synthesis of Amino Acids and Related Compounds, part 21.—Part 20: Y. Ozaki, S. Maeda, M. Miyoshi and K. Matsumoto, Synthesis, 216 (1979).We would like to acknowledge Dr I. Chibata for his encouragement in this work.     

12-Hydroxy-E-γ-bisabolene,a new sesquiterpene alcohol from a Caribbean sea whip of the genusPseudopterogorgia (Gorgonacea,Cnidaria)

Summary A new sesquiterpene alcohol, 12-hydroxy-E--bisabolene, is reported from an undescribed Caribbean sea whip of the genusPseudopterogorgia. The structure of this new alcohol was established based upon spectral analyses and through chemical interconversions.Acknowledgment. This research was supported by NOAA, Office of Sea Grant, Department of Commerce, under grant NA80AA-D-00120, and in part by the California State Resources Agency, project R/MP-22. The U.S. Government is authorized to reproduce and distribute reprints. We wish to acknowledge the mass spectral support provided by the Bioorganic Biomedical Mass Spectrometry Resource Center, University of California, San Francisco (A.L. Burlingame, Director) which is supported through NIH grant RR00719.     

Einstein’s quantum theory of the monatomic ideal gas: non-statistical arguments for a new statistics

In this article, we analyze the third of three papers, in which Einstein presented his quantum theory of the ideal gas of 1924–1925. Although it failed to attract the attention of Einstein’s contemporaries and although also today very few commentators refer to it, we argue for its significance in the context of Einstein’s quantum researches. It contains an attempt to extend and exhaust the characterization of the monatomic ideal gas without appealing to combinatorics. Its ambiguities illustrate Einstein’s confusion with his initial success in extending Bose’s results and in realizing the consequences of what later came to be called Bose–Einstein statistics. We discuss Einstein’s motivation for writing a non-combinatorial paper, partly in response to criticism by his friend Ehrenfest, and we paraphrase its content. Its arguments are based on Einstein’s belief in the complete analogy between the thermodynamics of light quanta and of material particles and invoke considerations of adiabatic transformations as well as of dimensional analysis. These techniques were well known to Einstein from earlier work on Wien’s displacement law, Planck’s radiation theory and the specific heat of solids. We also investigate the possible role of Ehrenfest in the gestation of the theory.     

Is the EHT black hole experiment a new experiment in the guise of an old experiment?

This paper analyzes the experiment presented in 2019 by the Event Horizon Telescope (EHT) Collaboration that unveiled the first image of the supermassive black hole at the center of galaxy M87. The intended aim of the paper is to assess whether the EHT Collaboration has made an “inference to the best explanation” (IBE) to conclude that the data effectively confirm the hypothesis that the object at the center of M87 is in fact a supermassive Kerr rotating black hole. I demonstrate that the EHT Collaboration has applied an IBE. It is shown that the hypothesis that at the center of M87 there is a supermassive Kerr rotating black hole was already the best explanation at the time in which the 2017 EHT experiment was conducted. My analysis is intertwined with considerations on realist and empiricist interpretations of IBE, which are used to assess whether the conclusion that the object at the center of M87 is a Kerr rotating black hole implies holding a realist commitment with respect to such object.     

The opposed influences ofβ-adrenergic stimulation and adenosine on the frequency-force relationship of isolated left atria of guinea-pigs

Summary The normal frequency-force relationship of left guinea-pig atria can be largely suspended when strong -adrenergic stimulation by orciprenaline is antagonized by the negative inotropic effect of adenosine, so that contraction amplitude is nearly equal at an intermediate level over a wide range of stimulation rates. Curves obtained with a new method for recording continuous frequency-force loops are presented.     

15-Deoxy-Δ12,14-prostaglandin-J2 reveals a new pVHL-independent, lysosomal-dependent mechanism of HIF-1α degradation

Hypoxia-inducible factor-1α (HIF-1α) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL) and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Δ^12,14-prostaglandin-J₂ (15d-PGJ₂) accumulate HIF-1α in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We found that 15d-PGJ₂ induced an over-accumulation of HIF-1α in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain them. We have identified a new lysosomal-dependent mechanism of HIF-1α degradation as a target for 15d-PGJ₂ based on: (1) HIF-1α colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ₂ inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation of HIF-1α in 15d-PGJ₂-treated cells. Therefore, expression of HIF-1α is also modulated by lysosomal degradation.     

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002