The in vivo expression of the globin genes of theβ cistron in γ-,δ-, andδβ-thalassemia heterozygotes

There is considerable evidence suggesting that the switch from to and chain production after birth is due, in part, to silencing of the genes by stage-specific factors which bind to their promoters and to the competition from the adult ( and ) genes for a common enhancer element located in the locus control region. As a consequence one can expect that the increased Hb F production in adults with hereditary persistence of fetal hemoglobin or -thalassemia is directed mainly by -globin genes in cis to the deletion(s) responsible for these conditions. Here we review data on heterozygotes with -, -, or -thalassemia, who also had an^AT mutation, in cis or in trans, which was used as a marker of gene expression. The results show that a deletion affecting adult genes favors the expression of genes in cis, while the deletion of a single gene does not affect the expression of the gene in cis but leads to a faster switch postnatally.     

Cerivastatin: a cellular and molecular drug for the future?

The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market - the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future. Received 29 May 2002; received after revision 23 August 2002; accepted 26 August 2002 RID="*" ID="*"Corresponding author.     

A place for pragmatism in the dynamics of reason?

In Dynamics of Reason Michael Friedman proposes a kind of synthesis between the neokantianism of Ernst Cassirer, the logical empiricism of Rudolf Carnap, and the historicism of Thomas Kuhn. Cassirer and Carnap are to take care of the Kantian legacy of modern philosophy of science, encapsulated in the concept of the relativized a priori and the globally rational or continuous evolution of scientific knowledge, while Kuhn’s role is to ensure that the historicist character of scientific knowledge is taken seriously. More precisely, Carnapian linguistic frameworks, guarantee that the evolution of science proceeds in a rational manner locally, while Cassirer’s concept of an internally defined conceptual convergence of empirical theories provides the means to maintain the global continuity of scientific reason. In this paper it is argued that Friedman’s Neokantian account of scientific reason based on the concept of the relativized a priori underestimates the pragmatic aspects of the dynamics of scientific reason. To overcome this shortcoming, I propose to reconsider C.I. Lewis’s account of a pragmatic priori, recently modernized and elaborated by Hasok Chang. This may be considered as a first step to a dynamics of an embodied reason, less theoretical and more concrete than Friedman’s Neokantian proposal.     

The structure of human interferon-β: implications for activity

Interferons (IFNs) are potent extracellular protein mediators of host defence and homoeostasis. This article reviews the structure of human IFN-β (HuIFN-β), in particular in relation to its activity. The recently determined crystal structure of HuIFN-β provides a framework for understanding of the mechanism of differentiation of type I IFNs by their common receptor. Insights are generated by comparison with the structures of other type I IFNs and from the interpretation of existing mutagenesis data. The details of the observed carbohydrate structure, together with biochemical data, implicate the glycosylation of HuIFN-β, which is uncommon among type I IFNs, as an important factor in the solubility, stability and, consequently, activity of the protein. Finally, these structural implications are discussed in the context of the clinical use of HuIFN-β. Received 12 June 1998; received after revision 16 July 1998; accepted 16 July 1998     

Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.     

A specialized mitochondrial molecular chaperone system:¶A role in formation of Fe/S centers

Mitochondria contain a specialized system of molecular chaperones that plays a critical role in the biogenesis of Fe/S centers. This Hsp70:J-protein system shows many similarities to the system found in bacteria, but the precise role of neither chaperone system has been defined. However, evidence to date suggests an interaction with the scaffold protein on which a transient Fe/S center is assembled, and thus implies a role in either assembly of the center or its transfer to recipient proteins.     

Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease

Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin, (iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize preformed Aβ fibrils. Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006     

A molecular pin to study the dynamics of β-barrel formation in pore-forming toxins on erythrocytes: a sliding model

γ-Hemolysins are pore-forming toxins which develop from water-soluble monomers by combining two different ‘albeit homologous’ proteins. They form oligomeric pores in both cell and model membranes by undergoing a still poorly understood conformational rearrangement in the stem region. The stem is formed by three β-strands, folded onto the core of the soluble protein and completely extended in the pore. We propose a new model to explain such a process. Seven double-cysteine mutants were developed by inserting one cysteine on the stretch that links the β-hairpin to the core of the protein and another on different positions along the β-strands. The membrane bound protein was blocked in a non-lytic state by S–S bond formation. Six mutants were oxidized as inactive intermediates, but became active after adding DTT. These results demonstrate that the stem extension can be temporarily frozen and that the β-barrel formation occurs by β-strand concerted step-by-step sliding. Received 22 October 2007; received after revision 15 November 2007; accepted 19 November 2007     

A suggested mechanism for the action of choline esters on animal organs,inferred from a study of the effect of choline-,β-methylcholine-, and thiocholine-esters

Résumé Le mécanisme d'action des esters carboxyliques de la choline commence, probablement, par une hydrolyse enzymatique provoquée par une des cholinestérases. Les produits de l'hydrolyse réagissent avec un facteur inconnu, dont la spécificité est cependant définissable par la structure du résidu cholinique.     

Turning points in the evolution of peroxidase–catalase superfamily: molecular phylogeny of hybrid heme peroxidases

Heme peroxidases and catalases are key enzymes of hydrogen peroxide metabolism and signaling. Here, the reconstruction of the molecular evolution of the peroxidase–catalase superfamily (annotated in pfam as PF00141) based on experimentally verified as well as numerous newly available genomic sequences is presented. The robust phylogenetic tree of this large enzyme superfamily was obtained from 490 full-length protein sequences. Besides already well-known families of heme b peroxidases arranged in three main structural classes, completely new (hybrid type) peroxidase families are described being located at the border of these classes as well as forming (so far missing) links between them. Hybrid-type A peroxidases represent a minor eukaryotic subfamily from Excavates, Stramenopiles and Rhizaria sharing enzymatic and structural features of ascorbate and cytochrome c peroxidases. Hybrid-type B peroxidases are shown to be spread exclusively among various fungi and evolved in parallel with peroxidases in land plants. In some ascomycetous hybrid-type B peroxidases, the peroxidase domain is fused to a carbohydrate binding (WSC) domain. Both here described hybrid-type peroxidase families represent important turning points in the complex evolution of the whole peroxidase–catalase superfamily. We present and discuss their phylogeny, sequence signatures and putative biological function.     

Completion of the natural groups of ergot alkaloids: Syntheses and pharmacological profiles ofβ-ergosine andβ-ergoptine

Summary The syntheses and pharmacological potencies of -ergosine and -ergoptine, the missing links in the natural groups of ergot peptide alkaloids are described.86th communication on ergot alkaloids.     

Dopamine-β-hydroxylase,adrenaline, noradrenaline and dopamine in the venous blood of adrenal gland of man: A comparison with levels in the periphery of the circulation

Summary In 10 human subjects plasma dopamine--hydroxylase activity was found in the adrenal vein blood to be as high as in the periphery of the circulation. Adrenaline concentration in the adrenal vein blood was in the mean 170 times, noradrenaline concentration 11 times and dopamine concentration little higher than levels in the periphery.This study was supported by the Deutsche Forschungsgemeinschaft.     

Heterologous immunoadsorption in the purification of enzymes: N-acetyl-β-glucosaminidase

Summary An immunoadsorbent column was prepared using a specific antibody toN-acetyl--glucosaminidase of human origin. Although no precipitating activity of the antisera was found with mouse or rat liver extracts, enzyme was easily eluted from the column which provided about 50fold, single-step purifications of these heterologous enzymes.     

β-Adrenergic stimulation of androgen production by fetal mouse Leydig cells in primary culture

Summary The responsiveness of fetal mouse Leydig cells to catecholamines (epinephrine, norepinephrine), a-agonist agent (L-isoproterenol) and hCG was investigated in vitro. Fetal Leydig cells when freshly isolated were unable to respond to L-isoproterenol (10^–5M). However, L-isoproterenol, epinephrine and norepinephrine significantly stimulated androgen production by fetal Leydig cells after 24 h of primary culture. Androgen production was increased in both conditions and to a greater extent by hCG. Propranolol blocked the stimulatory effect of L-isoproterenol and epinephrine. It is concluded that catecholamines can regulate fetal testosterone biosynthesis.     

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.