Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.     

Interferon-dependent induction of mRNA activity for (2'-5')oligo-isoadenylate synthetase

At least three different enzymes involved in the regulation of protein synthesis are induced in a variety of cells by interferon (IFN). Sensitive assays for these enzymes have been developed and used to establish the specificity, dose dependence and time course of their induction by IFN. One of these enzymes, the oligo-isoadenylate synthetase E, whose product (2'-5')pppApApA activates the latent ribonuclease F, is increased over 50-fold after IFN treatment. We describe here the assay for an mRNA from IFN-treated mouse L cells, that produces oligo-isoadenylate synthetase activity when injected into Xenopus oocytes. This mRNA is found in the cells only after exposure to IFN. The mRNA increases in mouse L cells with the same time course as the enzyme activity itself. In particular, there is a 3-h lag period between IFN addition and the onset of enzyme and mRNA accumulation. Using anti-IFN antibodies, we show that during this lag period the continued interaction of IFN with the cells is necessary for the full induction of the oligo-isoadenylate synthetase.     

Ecdysterone: an insect moulting hormone fromAchyranthes aspera (amaranthaceae)

Résumé L'ecdystérone, hormone de mue des insectes a été extraite de l'Achyranthes aspera et identifiée par des méthodes chromatographiques et spectroscopiques.     

Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas

The production of high-affinity protective antibodies requires somatic hypermutation (SHM) of the antibody variable (V)-region genes. SHM is characterized by a high frequency of point mutations that occur only during the centroblast stage of B-cell differentiation. Activation-induced cytidine deaminase (AID), which is expressed specifically in germinal-centre centroblasts, is required for this process, but its exact role is unknown. Here we show that AID is required for SHM in the centroblast-like Ramos cells, and that expression of AID is sufficient to induce SHM in hybridoma cells, which represent a later stage of B-cell differentiation that does not normally undergo SHM. In one hybridoma, mutations were exclusively in G*C base pairs that were mostly within RGYW or WRCY motifs, suggesting that AID has primary responsibility for mutations at these nucleotides. The activation of SHM in hybridomas indicates that AID does not require other centroblast-specific cofactors to induce SHM, suggesting either that it functions alone or that the factors it requires are expressed at other stages of B-cell differentiation.     

Effect of pancreatic secretions upon ileal disaccharidase activities of neonatal miniature pigs

Summary Mechanisms by which pancreatic secretions influence disaccharidase activities in the distal small intestine have been investigated in 1-week-old miniature pigs. Using a combination of biochemical, cytochemical and morphological techniques it has been found that the decrease in lactase specific activity is due solely to a reduction in villus surface area. By contrast, the increased sucrase-isomaltase activities, which occur despite the reduction in villus surface area, are due entirely to increased enzyme expression during enterocyte differentiation.     

Action of fully co-ordinated 1,10-phenanthroline transition metal chelates on the guinea-pig isolated atrium

Zusammenfassung Nachweis, dass vollkoordinierte zweiwertige Kupfer- und Nickelchelate des 3,4,7,8-Tetramethyl-1,10-phenanthrolins Muskelkraft, wie auch Kontraktionsgeschwindigkeit des isolierten Meerschweinchen Atriums, sowie H³-Noradrenalin- und Metabolitenausfluss vermehren. Die durch Chelate veranlasste Senkung des Noradrenalins konnte durch Fluoreszenz-Histochemie bestätigt werden.

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This work was commenced in the Department of Pharmacology, University of Melbourne and was presented in part by H. G. in November 1972 in partial fulfilment for the degree of B. Sc. (Hons) in the University of Melbourne.