Late Pleistocene microtine rodents from Snake Creek Burial Cave, White Pine County, Nevada

A total of 395 microtine rodent specimens recovered from Snake Creek Burial Cave (SCBC) are referred to Microtus sp. and Lemmiscus curtatus . Radiocarbon and Uranium series dates indicated an age for these fossils of between 9460 ± 160 yr. B.P. and 15,100 ± 700 yr. B.P. The sample of lower first molars of Lemmiscus includes 4-, 5-, and 6-closed triangle morphotypes. Earlier reports of the 4-closed triangle morphotype are from Irvingtonian deposits in Colorado, Nevada, and New Mexico and from early Rancholabrean deposits in Washington. The morphotype is not known in living populations of Lemmiscus . SCBC specimens constitute the youngest record of the 4-closed triangle morphotype and are the only specimens reported from the late Rancholabrean. The time of disappearance of Lemmiscus with this molar morphology is unknown, but populations with this morphotype possibly became extinct at or near the end of the Pleistocene.     

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.     

Mapping of the class II region of the human major histocompatibility complex by pulsed-field gel electrophoresis

The class II region of the human major histocompatibility complex (MHC) encodes a polymorphic set of cell surface glycoproteins involved in the regulation of the immune response. Each glycoprotein is a heterodimer composed of a alpha-chain of relative molecular mass (Mr) 34,000 (34 K) and a beta-chain of Mr = 28K. The products of the class II region have been characterized by the mixed lymphocyte reaction, serology, primed lymphocyte typing and DNA cloning. DR, DQ and DP, three subregions containing both alpha- and beta-chains, and two additional loci, DZ alpha and DO beta, locate this gene cluster on the short arm of chromosome 6. The precise genomic organization of these loci have been difficult to determine. Here we describe the use of pulsed-field gel electrophoresis together with restriction endonucleases having few genomic restriction sites and Southern blotting, to determine the order of the subregions and to derive a map for the human class II region. The order of these loci is similar to that of the homologous loci in the murine class II region. Our study establishes the use of pulsed-field gel electrophoresis in mapping large regions of the genome in higher eukaryotes.     

Antihypertensive activity of 7-azaindole-3-acetamidoxime and indole-1-acetamidoxime

Zusammenfassung 7-Azaindol-3-acetamidoxim (I) und Indol-1-acetamidoxim (II) normalisieren hohen Blutdruck von Ratten und Hunden. Die blutdrucksenkende Wirkung von I scheint auf der Freisetzung von Brenzcatechinaminen und der Erschöpfung ihrer Depots zu beruhen. Die Wirkung von II findet zur Zeit keine befriedigende Erklärung.