Indoxyl derivatives of drug metabolites

Summary Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl. Such derivatives have not hitherto been encountered in drug metabolism.     

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.     

Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression

Although proteins fulfil most of the requirements that biology has for structural and functional components such as enzymes and receptors, RNA can also serve in these capacities. For example, RNA has sufficient structural plasticity to form ribozyme and receptor elements that exhibit considerable enzymatic power and binding specificity. Moreover, these activities can be combined to create allosteric ribozymes that are modulated by effector molecules. It has also been proposed that certain messenger RNAs might use allosteric mechanisms to mediate regulatory responses depending on specific metabolites. We report here that mRNAs encoding enzymes involved in thiamine (vitamin B(1)) biosynthesis in Escherichia coli can bind thiamine or its pyrophosphate derivative without the need for protein cofactors. The mRNA-effector complex adopts a distinct structure that sequesters the ribosome-binding site and leads to a reduction in gene expression. This metabolite-sensing regulatory system provides an example of a 'riboswitch' whose evolutionary origin might pre-date the emergence of proteins.     

Coenzyme Q is an obligatory cofactor for uncoupling protein function

Uncoupling proteins (UCPs) are thought to be intricately controlled uncouplers that are responsible for the futile dissipation of mitochondrial chemiosmotic gradients, producing heat rather than ATP. They occur in many animal and plant cells and form a subfamily of the mitochondrial carrier family. Physiological uncoupling of oxidative phosphorylation must be strongly regulated to avoid deterioration of the energy supply and cell death, which is caused by toxic uncouplers. However, an H+ transporting uncoupling function is well established only for UCP1 from brown adipose tissue, and the regulation of UCP1 by fatty acids, nucleotides and pH remains controversial. The failure of UCP1 expressed in Escherichia coli inclusion bodies to carry out fatty-acid-dependent H+ transport activity inclusion bodies made us seek a native UCP cofactor. Here we report the identification of coenzyme Q (ubiquinone) as such a cofactor. On addition of CoQ10 to reconstituted UCP1 from inclusion bodies, fatty-acid-dependent H+ transport reached the same rate as with native UCP1. The H+ transport was highly sensitive to purine nucleotides, and activated only by oxidized but not reduced CoQ. H+ transport of native UCP1 correlated with the endogenous CoQ content.     

喀斯特自然土壤中AM真菌对先锋植物根系的影响

【目的】研究丛枝菌根(Arbuscular mycorrhiza，AM)真菌在喀斯特自然土壤条件下对喀斯特先锋草本植物根系的影响。【方法】通过自然土接种AM真菌(N)、灭菌土接种AM真菌(M)及灭菌土壤对照(S)共3种土壤处理，种植喀斯特先锋植物狗尾草(Setaria viridis)、荩草(Arthraxon hispidus)、鬼针草(Bidens pilosa)及狼杷草(Bidens tripartita)，并测定它们的根系生物量、根长、根表面积、根体积、根平均直径、根尖数及根分枝数。【结果】荩草、鬼针草及狼杷草在N处理及M处理下具有较高的菌根侵染率，狗尾草的菌根侵染率较低。与S处理相比，M处理下AM真菌明显提高了荩草、鬼针草及狼杷草的根系生物量、根长、根表面积、根体积、根尖数、根分枝数及组织密度，降低了根平均直径、比根长、比根面积及比根体积；与M处理相比，N处理明显降低了荩草、鬼针草及狼杷草的根系生物量、根长、根表面积、根体积、根尖数、根分枝数及组织密度，提高了比根长、比根面积及比根体积，但对根平均直径无明显影响。【结论】荩草、鬼针草及狼杷草具有较高菌根侵染率，能与AM真菌共生获得更加发达的根系，而自然土壤削弱了AM真菌对荩草、鬼针草及狼杷草根系生长的促进作用。     

Indoxyl derivatives of drug metabolites

Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl. Such derivatives have not hitherto been encountered in drug metabolism.     

The accuracy of extrapolation (time series) methods: Results of a forecasting competition

In the last few decades many methods have become available for forecasting. As always, when alternatives exist, choices need to be made so that an appropriate forecasting method can be selected and used for the specific situation being considered. This paper reports the results of a forecasting competition that provides information to facilitate such choice. Seven experts in each of the 24 methods forecasted up to 1001 series for six up to eighteen time horizons. The results of the competition are presented in this paper whose purpose is to provide empirical evidence about differences found to exist among the various extrapolative (time series) methods used in the competition.