(−)-Δ8-tetrahydrocannabinol: Two novel in vitro metabolites

Zusammenfassung (–)-⁸-Tetrahydrocannabinol ist einer der Aktivstoffe in Marihuana (Cannabis sativa L.). Inkubation dieser Verbindung mit der überstehenden Zentrifugationsfraktion (9000g) aus männlicher Hundeleber ergab zwei Hauptmetaboliten, welche durch Massenspektrometrie und Kernresonanzspektroskopie identifiziert wurden. Den beiden Verbindungen werden die Strukturen des 1-Hydroxy-⁸-tetrahydrocannabinols und des 3-Hydroxy-⁸-tetrahydrocannabinols zugeordnet.     

Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors

Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.     

Closing gaps in the human genome with fosmid resources generated from multiple individuals

The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.     

Fine-scale structural variation of the human genome

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.     

World Year of Physics: a direct test of E=mc2

One of the most striking predictions of Einstein's special theory of relativity is also perhaps the best known formula in all of science: E=mc(2). If this equation were found to be even slightly incorrect, the impact would be enormous--given the degree to which special relativity is woven into the theoretical fabric of modern physics and into everyday applications such as global positioning systems. Here we test this mass-energy relationship directly by combining very accurate measurements of atomic-mass difference, Delta(m), and of gamma-ray wavelengths to determine E, the nuclear binding energy, for isotopes of silicon and sulphur. Einstein's relationship is separately confirmed in two tests, which yield a combined result of 1-Delta(mc2)/E=(-1.4+/-4.4)x10(-7), indicating that it holds to a level of at least 0.00004%. To our knowledge, this is the most precise direct test of the famous equation yet described.