A Sultone Route to the Antileukemic 1 ,10-Seco-Eudesmanolides （ - ）-Eriolanin and （ - ）-Eriolangin

The highly oxygenated 1,10-seco-eudesmanolides （ - ）-eriolanin （ 1 ） and （ - ）-eriolangin （2） isolated from the plant Eriophyllum lanatum （Asteraceae） inhibit the growth of the human KB tumor cell line in vitro and additionally display a significant antileukemie activity in vivo in mice （Scheme 1 ）. Using novel methods for the synthetic elaboration of sultones, the first enantioseleetive total syntheses of 1 and 2 have been accomplished, which also established the hitherto unknown absolute configuration of these natural produets.     

Mathematical Models and Reality: A Constructivist Perspective

To explore the relation between mathematical models and reality, four different domains of reality are distinguished: observer-independent reality (to which there is no direct access), personal reality, social reality and mathematical/formal reality. The concepts of personal and social reality are strongly inspired by constructivist ideas. Mathematical reality is social as well, but constructed as an autonomous system in order to make absolute agreement possible. The essential problem of mathematical modelling is that within mathematics there is agreement about ‘truth’, but the assignment of mathematics to informal reality is not itself formally analysable, and it is dependent on social and personal construction processes. On these levels, absolute agreement cannot be expected. Starting from this point of view, repercussion of mathematical on social and personal reality, the historical development of mathematical modelling, and the role, use and interpretation of mathematical models in scientific practice are discussed.     

The DNA sequence of human chromosome 21

Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1 in 700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumours. Here we report the sequence and gene catalogue of the long arm of chromosome 21. We have sequenced 33,546,361 base pairs (bp) of DNA with very high accuracy, the largest contig being 25,491,867 bp. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 kilobases. Thus, we achieved 99.7% coverage of 21q. We also sequenced 281,116 bp from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes and 59 pseudogenes.     

Identifiablity of Models for Clusterwise Linear Regression

The model choice and the interpretation of the parameters are discussed as well as the use of the identifiability concept for fixed partition models. The concept is generalized to "partial identifiability".     

Emergent reduction of electronic state dimensionality in dense ordered Li-Be alloys

High pressure is known to influence electronic structure and crystal packing, and can in some cases even induce compound formation between elements that do not bond under ambient conditions. Here we present a computational study showing that high pressure fundamentally alters the reactivity of the light elements lithium (Li) and beryllium (Be), which are the first of the metals in the condensed state and immiscible under normal conditions. We identify four stoichiometric Li(x)Be(1-x) compounds that are stable over a range of pressures, and find that the electronic density of states of one of them displays a remarkable step-like feature near the bottom of the valence band and then remains almost constant with increasing energy. These characteristics are typical of a quasi-two-dimensional electronic structure, the emergence of which in a three-dimensional environment is rather unexpected. We attribute this observation to large size differences between the ionic cores of Li and Be: as the density increases, the Li cores start to overlap and thereby expel valence electrons into quasi-two-dimensional layers characterized by delocalized free-particle-like states in the vicinity of Be ions.     

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.     

A Sultone Route to the Antileukemic 1 ,1O-Seco-Eudesmanolides (-)-Eriolanin and (-)-Eriolangin

1Introduction The highly oxygenated 1,10-seco-eudesmanolides ( - )-eriolanin (1) and ( - )-eriolangin (2) isolated from the plant Eriophyllum lanatum (Asteraceae) inhibit the growth of the human KB tumor cell line in vitro and additionally display a significant antileukemic activity in vivo in mice (Scheme 1)[1]. Using novel methods for the synthetic elaboration of sultones[2], the first enantioselective total syntheses of 1 and 2 have been accomplished, which also established the hitherto unknown absolute configuration of these natural products[3].