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].     

Structural insight into function and regulation of carnitine palmitoyltransferase

The control of fatty acid translocation across the mitochondrial membrane is mediated by the carnitine palmitoyltransferase (CPT) system. Modulation of its functionality has simultaneous effects on fatty acid and glucose metabolism. This encourages use of the CPT system as drug target for reduction of gluconeogenesis and restoration of lipid homeostasis, which are beneficial in the treatment of type 2 diabetes mellitus and obesity. Recently, crystal structures of CPT-2 were determined in uninhibited forms and in complexes with inhibitory substrate-analogs with anti-diabetic properties in animal models and in clinical studies. The CPT-2 crystal structures have advanced understanding of CPT structure–function relationships and will facilitate discovery of novel inhibitors by structure-based drug design. However, a number of unresolved questions regarding the biochemistry and pharmacology of CPT enzymes remain and are addressed in this review.     

Firing patterns of motor units in normal rats

Skeletal muscles consist of motor units which may differ considerably in contractile properties and types of usage. Some units participate mainly in relatively rare, quick movements and contract rapidly and are easily fatigued (type FF); others contribute to the maintenance of posture and hence contract slowly and are fatigue-resistant (type S), while others are both fast and fatigue-resistant (type FR). Our understanding of motor control mechanisms and the dependence of contractile properties on usage would be enhanced if more quantitative information were available concerning the firing patterns of individual motor units during normal motor behaviour. Therefore, we have made continuous recordings for extended periods from single motor units in the fast extensor digitorum longus (edl) and the slow soleus (sol) muscle of freely moving adult rats. By counting the total number of discharges for each unit, and by determining the distributions of interspike intervals and the duration of the individual impulse trains, we have obtained information about firing rate, amount of use, modulation of muscle force and tonic and phasic behaviour for 16 motor units. We now report that these units fall into three classes apparently corresponding to type FF and FR in the edl muscle and type S in the soleus muscle.     

Fixed Point Clusters for Linear Regression: Computation and Comparison

In this paper an algorithm is developed, which aims to find all FPCs of a dataset corresponding to well separated linear regression subpopulations. Its ability to find such subpopulations under the occurence of outliers is compared to methods based on ML-estimation of mixture models by means of a simulation study. Furthermore, FPC analysis is applied to a real dataset.     

果蝇精子发生中CG15899的基因表达

为了检测在雄性果蝇中CG15899基因是否有特殊的表达,利用PCR的方法得到CG15899的基因片段,并用DIG标记PCR产物,将其与野生型雄性果蝇melanogaster的精巢进行原位杂交,最后在果蝇精巢的细胞质中产生了较强的信号．实验结果表明,CG15899基因在精原细胞和初级精母细胞中表达．     

Matter in Z3

In this paper, I will discuss a certain conception of matter that Aristotle introduces in Metaphysics Z3. It is often assumed that Aristotle came to distinguish between matter and form only in his physical writings, and that this lead to a conflict with the doctrine of primary substances in the Categories that he tries to resolve in Z3. I will argue that there is no such conflict. In Z3, Aristotle seems to suggest that matter is what is left over when we strip a thing of all its properties. I take it that he does not want us to strip away these properties by physical means or in our imagination. Rather, we are asked to strip a referring noun phrase of all its predicative parts. We are thus not supposed to be able to refer to something that has no qualities whatsoever, but to construct a phrase that refers to something that has properties without referring to its having them, and without implying which properties it has. The idea that there might be a way of referring to something definite without mentioning any of its qualities is platonic and it still underlies modern predicate logic. In Z3, Aristotle argues against this conception and thus against the basic idea of predicate logic. According to him, matter is at best an inseparable aspect of a primary substance, which substance is best referred to as a compound τóδε τι (“this such”). Matter is what the τóδε refers to as part of this phrase. But it cannot exist in separation from form, and we cannot refer to it by a separated term, without also referring to the substantial form of the substance of which it is an aspect.