Mikrobiologische Spaltung razemischer Steroide. Synthese vond-Aldosteron

Summary A racemic intermediate in the total synthesis ofd, l-aldosterone, thed, l-20-oxo-pregnene derivative I, was converted by incubation with a mold hydroxylating in the 21-position into thed-20-oxo-21-hydroxy-pregnene derivative II, whereas thel-antipode of the starting material remained unchanged. This stereospecific microbiological reaction, comprising a separation of racemic modifications, represents the last remaining step in the synthesis of naturald-aldosterone.Other microbiological conversions of racemic steroids, dehydrogenation and hydrogenation, were also shown to proceed only with thed-enantiomer, leaving thel-form of thed, l-substrate intact.The advantages of this new microbiological method for the resolution of racemic modifications during the total synthesis of steroids are discussed.     

Interaction between sugars and amino acids in intestinal absorption by rat,in vivo

Summary The inhibitory action ofl-leucine on the intestinal absorption ofd-glucose andd-galactose, as well as the inhibitory action ofd-galactose on the absorption ofl-leucine at various concentrations by rat small intestine has been studied. The further effect was more clearly evidenced when the medium was perfunded through the intestine in a closed circuit system using a peristaltic pump.     

Zur leukotaktischen Wirkung von Aminosäuren in Liquor cerebrospinalis

Summary Intercisternal injections of-aminobutyric acid,l-asparagin,l-glutamine,l-leucine andl-norleucine exert a strong leukotactic action and in dogs result after a short time in a maximum cell increase of 76,000/3 cells.     

The chemistry of the polymyxin antibiotics

Zusammenfassung Die Chemie der Polymyxine, einer Klasse von basischen Polypeptid-Antibiotika, begann 1954, als durch Gegenstromverteilung erstmals ein definierter Vertreter, das Polymyxin B₁ in reiner Form isoliert werden konnte (L. C.Craig). Partialhydrolyse mit Mineralsäuren führte zum Schluss, dass es sich um Cyclohepta- oder Cyclooctapeptide mit Seitenketten handelt, die, -Diaminobuttersäure (Dab) enthalten (W.Hausmann).Amidartige Verknüpfung der Seitenkette mit einer Fettsäure [(+)-6-Methyloctansäure (MOA) oder 6-Methylheptansäure (IOA)] (S.Wilkinson) verleiht diesen Antibiotika den Charakter von Invertseifen. Sie sind besonders gegen gramnegative Erreger wirksam. Schwierigkeiten bereiteten die Aufklärung der Verknüpfungsweise der Seitenkette (- oder-) und die Beantwortung der Frage, ob das Molekül nebend-Phenylalanin in der Ringsequenz noch einend-, -Diaminobuttersäurerest in Nachbarschaft zur Fettsäure in der Seitenkette enthält. Synthetische Versuche mitd-, -Diaminobuttersäure an dieser Stelle führten zu hochaktiven Produkten, die aber mit natürlichem Polymyxin B₁ nicht identisch waren. Entscheidende Fortschritte wurden mit dem bakteriellen Enzym Nagarse (T.Suzuki) erzielt, das schrittweise die Seitenkette bis zum Ringpeptid abbaut. Dabei ergab sich, dass den Polymyxinen die allgemeine Struktur eines Cycloheptapeptides mit-verknüpfter Seitenkette zukommt (Figur 4).Die Polymyxine B₁ E₁ (Colistin A) sowie Circulin A unterscheiden sich voneinander nur durch eine Variation in der gleichen Dipeptidsequenz des 7-gliedrigen Ringes. Die im Polymyxin B₁ vorhandene Dipeptidsequenzd-Phe-l-Leu ist in Polymyxin E₁ (Colistin A) durchd-Leu-l-Leu und in Circulin A durchd-Leu-Ll-Ile ersetzt. Im Polymyxin D₁ ist neben dem Ersatz der entsprechenden Sequenz durchl-Leu-l-Thr noch ein, -Diaminobuttersäurerest der Seitenkette durch eind-Serin ausgetauscht. Die entsprechenden Verbindungen mit dem Index 2 unterscheiden sich von denjenigen mit dem Index 1 durch einen Austausch der (+)-6-Methyloctansäure durch 6-Methylheptansäure.Die Struktur von Polymyxin B₁ E₁ und Circulin A konnte durch Totalsynthese gesichert werden (K.Vogler). Weitere Fortschritte in der Erforschung der Natur der noch unbekannten Vertreter sind in Kürze zu erwarten.     

Synthesis of L-4-amino-3-isoxazolidinone,the unnatural stereoisomer of cycloserine and its antibiotic activity

Zusammenfassung Eine direkte Synthese vonl- undd-Cycloserin ausl- undd-Serin wurde beschrieben. Die bakteriostatischen Effekte der drei Formen von Cycloserin (d-,l-unddl-) aufE. coli in synthetischem Medium wurden verglichen.     

Synthesis and structure of Fungisporin

Zusammenfassung Die Struktur von Fungisporin, eines Zyklopeptides aus Sporen verschiedener Spezies vonPenicillium undAspergillus-Arten, wird durch Synthese und Vergleich mit dem Naturprodukt als die eines Zyklotetrapeptides, cyclo-(l-Phe-d-Val-l-Val-d-Phe-), bewiesen.     

Verhütung der Hitzekoagulation von Serumproteinen durch Zucker

Summary Sixteen individuals of different types of sugars have been investigated as to their ability of inhibiting the visible heat coagulation of serum. When bovine serum was diluted with an equal amount of water and maintained at 70° C during half an hour, the following sugars were able to prevent coagulation in a minimum concentration of 5% per volume:l-arabinose,d-ribose,l-ascorbic acid, and digitoxose.     

Ligand recognition by the I domain-containing integrins

Seven of the integrin α subunits described to date, α ₁ , α ₂ , α _L , α _X , α _d , α _M and α _E , contain a highly conserved I (or A) domain of approximately 200 amino acid residues inserted near the amino-terminus of the subunit. As the result of a variety of independent experimental approaches, a large body of data has recently accumulated that indicates that the I domains are independent, autonomously folding domains capable of directly binding ligands that play a necessary and important role in ligand binding by the intact integrins. Recent crystallographic studies have elucidated the structures of recombinant α _M and α _L I domains and also delineated a novel divalent cation-binding motif within the I domains (metal ion-dependent adhesion site, MIDAS) that appears to mediate the divalent cation binding of the I domains and the I domain-containing integrins to their ligands.     

Über das Verhalten der optischen Isomeren von Adrenalin im Blut

Summary Demethylation ofl- andd-adrenaline was studied on narcotized catsin vivo.In metabolism of infusedl-adrenaline, formation of noradrenaline represents one first step.On the other hand, metabolism ofd-adrenaline does not show any intermediate formation of noradrenaline.     

Ein neues Alkaloid aus dem Mycel einesClaviceps purpurea-Stammes. Zur Biogenese von Ergocristin

Summary A new alkaloid from the lyophilized mycelia of aClaviceps purpurea strain, N-[N-(d-Lysergyl)-l-valyl]-l-phenylalanyl-d-prolin-lactam, has been isolated and characterized. From its fast methanolysis it is deduced that the previously reported N-(d-Lysergyl)-l-valinmethylester is actually an artefact. The biogenetic significance and its possible role in biogenesis of Ergocristine is discussed.     

Allometry of mammalian cellular oxygen consumption

In the 1930s, Max Kleiber and Samuel Brody established that the interspecies correlation between mammalian body mass and metabolic rate (αM^0.75) cannot be explained (solely) by whole body surface area (αM^0.66) to volume ratios. Metabolic considerations must also be taken into account. Decreases in the proportion of visceral organ mass to whole body mass can account for some of the whole body metabolic differences. However, superimposed upon these anatomical differences, the metabolism of tissues and cells has been demonstrated to decrease with increasing body mass. These decreases in oxygen consumption rates (with increasing body mass) in cells and tissues can be explained by a decrease in ATP turnover and mitochondrial density and an increase in mitochondrial functional efficiency (decrease in proton leak). The majority of the proton leak differences reflect differences in mitochondrial inner membrane surface area. Indeed, liver metabolism correlates directly with liver mitochondrial inner membrane surface area. Apart from being a significant contributor (~25 %) to basal metabolism, mitochondrial proton leak is a major factor determining the differences in basal metabolism between mammals of different body mass. Received 31 May 2000; received after revision 2 October 2000; accepted 14 November 2000     

Signal regulation by family conspiracy

The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors. This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP). DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus. Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000     

Ribonuclease 4, an evolutionarily highly conserved member of the superfamily

The structural and enzymatic properties of RNase 4 are reviewed. This RNase shows a much higher interspecies similarity (approximately 90%) than the other members of the RNase A superfamily. The enzyme is ubiquitous, with the highest amounts present in liver and lung. Its unique uridine specificity results from alterations in and around the pyrimidine-binding site. In particular, the shortened C-terminus and the side chains of Phe-42, Asp-80 and Arg-101 appear to be involved. RNase 4 binds tightly to the intracellular RNase inhibitor, with a K _d of 4 × 10⁻¹⁵ M.     

4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease

The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins. Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ _1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H₂O₂ modification of Aβ _1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ _1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s disease Received 26 September 2000; accepted 26 September 2000     

Stéréochimie d'acides grasα-hydroxylés isolés d'une souche deStreptomyces

Summary A strain ofStreptomyces contains a mixture (ca. 3:1) of 2d-hydroxy-12l-methyltetradecanoic and 2d-hydroxy-13-methyltetradecanoic acids; it has the same properties as a similar mixture prepared by synthesis.

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11e Communication sur la chimie des micro-organismes; 10e communication:C. Lacave, J. Asselineau etR. Toubiana, Europ. J. Biochem.2, 37 (1967).     

Curamycin. II. Structure of the hydrolysis products ‘curacin’ and ‘d-curamicose’

Zusammenfassung Curacin, die chlorhaltige Fraktion der milden Hydrolyse des Antibiotikums Curamycin, wurde durch ihre chemischen und physikalischen Eigenschaften als 4-O-Dichlor-iso-everninyl-2-deoxy-d-rhamnose aufgeklärt. Ausserl-Lyxose und 4-O-Methyl-d-fucose besitzt auch das Curamycin ein drittes Monosaccharid,d-Curamicose, welches als 2,6-Di-O-methyl-d-mannose identifiziert wurde.     

Effect ofl- andd-thyroxine on the supraoptic neurosecretory ganglion cells of the rat

Zusammenfassung Mittels grosser Dosen vonl- undd-Thyroxin erhielt man keine deutlichen Veränderungen in der Menge und Verteilung von neurosekretorischem Material in den Zellen des Nucleus supraopticus bei der männlichen Ratte. Das Volumen der Kerne dieser Zellen nahm dagegen zu, besonders bei mitl-Thyroxin behandelten Ratten. Diese Veränderungen sprechen für eine vermehrte neurosekretorische Aktivität dieser Zellen.

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This investigation was supported by a grant from Sigrid Jusélius Foundation, Helsinki. The authors wish also to express appreciation to Pharmacia Company, Sweden for generous supplies of Na-d-thyroxine used in this study, and to MissS. Nurminen for technical assistance.     

Sensitivity of univariate AR(1) time‐series forecasts near the unit root

We consider the linear time‐series model y_t=d_t+u_t(t=1,...,n), where d_t is the deterministic trend and u_t the stochastic term which follows an AR(1) process; u_t=θu_t−1+ϵ_t, with normal innovations ϵ_t. Various assumptions about the start‐up will be made. Our main interest lies in the behaviour of the l‐period‐ahead forecast y_n+1 near θ=1. Unlike in other studies of the AR(1) unit root process, we do not wish to ask the question whether θ=1 but are concerned with the behaviour of the forecast estimate near and at θ=1. For this purpose we define the sth (s=1,2) order sensitivity measure λ_l^(s) of the forecast y_n+1 near θ=1. This measures the sensitivity of the forecast at the unit root. In this study we consider two deterministic trends: d_t=β_t and d_t=β_t+β_tt. The forecast will be the Best Linear Unbiased forecast. We show that, when d_t=β_t, the number of observations has no effect on forecast sensitivity. When the deterministic trend is linear, the sensitivity is zero. We also develop a large‐sample procedure to measure the forecast sensitivity when we are uncertain whether to include the linear trend. Our analysis suggests that, depending on the initial conditions, it is better to include a linear trend for reduced sensitivity of the medium‐term forecast. Copyright © 2001 John Wiley & Sons, Ltd.     

Adaptation of intestinal amino acid transport

Zusammenfassung An evertierten Dünndarmsäcken (proximales Jejunum) erwachsener Ratten, die zwei Wochen lang eine proteinarme (13% Kasein) oder proteinreiche (88% Kasein) Diät erhalten hatten, wurde der aktive intestinale Transport vonl-Leuzin undd-Galaktose untersucht. Proteinreiche Ernährung führte zu einer Stimulierung desl-Leuzin-Transports, während derd-Galaktose-Transport dadurch unbeeinflusst blieb. Diese Befunde sprechen für eine spezifische Adaptation des intestinalen Aminosäurentransports an den Proteingehalt der Nahrung.     

Cellular and molecular aspects of Lyme arthritis

Lyme disease is a multisystem illness initiated upon infection with the spirochete Borrelia burgdorferi. Whereas the majority of patients who develop Lyme arthritis may be successfully treated with antibiotic therapy, about 10% go on to develop arthritis which persists for months to years, despite antibiotic therapy. Development of what we have termed treatment-resistant Lyme arthritis has previously been associated with both the presence of particular major histocompatibility complex class II alleles and immunoreactivity to the spriochetal outer surface protein A (OspA). Recently, we showed that patients with treatment-resistant Lyme arthritis, but not patients with other forms of arthritis, generate synovial fluid T cell responses to an immunodominant epitope of OspA and a highly homologous region of the human-lymphocyte-function-associated antigen-1α _L chain. Identification of a bacterial antigen capable of propagating an autoimmune response against a self-antigen provides a model of molecular mimicry in the pathogenesis of treatment-resistant Lyme arthritis. Received 21 December 1999; received after revision 10 April 2000; accepted 11 April 2000