A large nucleolar U3 ribonucleoprotein required for 18S ribosomal RNA biogenesis

Although the U3 small nucleolar RNA (snoRNA), a member of the box C/D class of snoRNAs, was identified with the spliceosomal small nuclear RNAs (snRNAs) over 30 years ago, its function and its associated protein components have remained more elusive. The U3 snoRNA is ubiquitous in eukaryotes and is required for nucleolar processing of pre-18S ribosomal RNA in all organisms where it has been tested. Biochemical and genetic analyses suggest that U3 pre-rRNA base-pairing interactions mediate endonucleolytic pre-rRNA cleavages. Here we have purified a large ribonucleoprotein (RNP) complex from Saccharomyces cerevisiae that contains the U3 snoRNA and 28 proteins. Seventeen new proteins (Utp1 17) and Rrp5 were present, as were ten known components. The Utp proteins are nucleolar and specifically associated with the U3 snoRNA. Depletion of the Utp proteins impedes production of the 18S rRNA, indicating that they are part of the active pre-rRNA processing complex. On the basis of its large size (80S; calculated relative molecular mass of at least 2,200,000) and function, this complex may correspond to the terminal knobs present at the 5' ends of nascent pre-rRNAs. We have termed this large RNP the small subunit (SSU) processome.     

Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension.

The angiotensin converting enzyme (ACE) is a key component of the renin angiotensin system that contributes to the regulation of blood pressure (BP). Recent demonstration of linkage between the ACE locus and elevated BP in a rat model of hypertension has further emphasized ACE as a candidate gene in human hypertension. We report the localization of the ACE gene on the genetic map of chromosome 17, and identify an extremely polymorphic marker at the human growth hormone (hGH) locus which shows no recombination with ACE. We have found no evidence to support linkage between the ACE locus and hypertension, which suggests that mutations at the ACE locus do not commonly contribute to the pathogenesis of hypertension in our test population.     

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.     

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10?? and two loci with a combined P < 5 × 10??). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10??). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.     

Interleukin-2 production used to detect antigenic peptide recognition by T-helper lymphocytes from asymptomatic HIV-seropositive individuals

T lymphocytes from mice and healthy humans immunized against the human immunodeficiency virus (HIV) envelope have recently been shown to recognize two antigenic regions of the gp160 HIV-envelope protein which have been located on the basis of amphipathicity. In HIV-infected humans, T-cell proliferative responses are lost soon after infection. Here we demonstrate that interleukin-2 production is often retained even when proliferative activity is absent, and that it can be used to monitor T-helper cell responses by HIV-seropositive donors. We use this approach to investigate the T-helper cell response of 42 asymptomatic HIV-seropositive patients to four synthetic gp160 peptides and to influenza A virus, an antigen requiring intact CD4 T-helper cell function. As many as 67% of the HIV-seropositive donors who retain responsiveness to influenza A virus respond to a single peptide, and 85-90% responded to at least one of the peptides.