Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease

Amyloid B-protein/amyloid A4 is a peptide present in the neuritic plaques, neurofibrillary tangles and cerebrovascular deposits in patients with Alzheimer's disease and Down's syndrome (trisomy 21) and may be involved in the pathogenesis of Alzheimer's disease. Recent molecular genetic studies have indicated that amyloid protein is encoded as part of a larger protein by a gene on human chromosome 21 (refs 6-9). The amyloid protein precursor (APP) gene is expressed in brain and in several peripheral tissues, but the specific biochemical events leading to deposition of amyloid are not known. We have now screened complementary DNA libraries constructed from peripheral tissues to determine whether the messenger RNA encoding APP in these tissues is identical to that expressed in brain, and we identify a second APP mRNA that encodes an additional internal domain with a sequence characteristic of a Kunitz-type serine protease inhibitor. The alternative APP mRNA is present in both brain and peripheral tissues of normal individuals and those with Alzheimer's disease, but its pattern of expression differs from that of the previously reported APP mRNA.     

Insulin stimulation of glucose uptake can be mediated by diacylglycerol in adipocytes

An early effect of insulin in adipocytes is to stimulate glucose uptake. The increased uptake appears to be due to mobilization of glucose transporters from an intracellular location to the plasma membrane and to enhanced intrinsic activity of the transporters. Little is known about the insulin-generated signals causing these changes. Phorbol esters have been shown to mimic the insulin effect, but phosphorylation of the transporter does not seem to be involved. A phospho-oligosaccharide was recently shown to mimic the effects of insulin on protein phosphorylation, suggesting that it could be a mediator for some intracellular metabolic effects of the hormone, but it did not affect glucose uptake. A diacyglycerol is produced in the plasma membrane in conjunction with the generation of the phospho-oligosaccharide. Here I show that added 1,2-diacylglycerols potently increase glucose transporter-mediated uptake of glucose in rat adipocytes, but without activation of protein kinase C.     

Resolution of quantitative traits into Mendelian factors by using a complete linkage map of restriction fragment length polymorphisms

The conflict between the Mendelian theory of particulate inheritance and the observation of continuous variation for most traits in nature was resolved in the early 1900s by the concept that quantitative traits can result from segregation of multiple genes, modified by environmental effects. Although pioneering experiments showed that linkage could occasionally be detected to such quantitative trait loci (QTLs), accurate and systematic mapping of QTLs has not been possible because the inheritance of an entire genome could not be studied with genetic markers. The use of restriction fragment length polymorphisms (RFLPs) has made such investigations possible, at least in principle. Here, we report the first use of a complete RFLP linkage map to resolve quantitative traits into discrete Mendelian factors, in an interspecific back-cross of tomato. Applying new analytical methods, we mapped at least six QTLs controlling fruit mass, four QTLs for the concentration of soluble solids and five QTLs for fruit pH. This approach is broadly applicable to the genetic dissection of quantitative inheritance of physiological, morphological and behavioural traits in any higher plant or animal.     

Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate

The generation of second messengers from the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdInsP2) by phosphoinositidase C has been implicated in the mediation of cellular responses to a variety of growth factors and oncogene products. The first step in the production of PtdInsP2 from phosphatidylinositol (PtdIns) is catalysed by PtdIns kinase. A PtdIns kinase activity has been found to associate specifically with several oncogene products, as well as with the platelet-derived growth factor (PDGF) receptor. We have previously identified two biochemically distinct PtdIns kinases in fibroblasts, and have found that only one of these, designated type I, specifically associates with activated tyrosine kinases. We have now characterized the site on the inositol ring phosphorylated by type I PtdIns kinase, and find that this kinase specifically phosphorylates the D-3 ring position to generate a novel phospholipid, phosphatidylinositol-3-phosphate (PtdIns(3)P). In contrast, the main PtdIns kinase in fibroblasts, designated type II, specifically phosphorylates the D-4 position to produce phosphatidylinositol-4-phosphate (PtdIns(4)P), previously considered to be the only form of PtdInsP. We have also tentatively identified PtdIns(3)P as a minor component of total PtdInsP in intact fibroblasts. We propose that type I PtdIns kinase is responsible for the generation of PtdIns(3)P in intact cells, and that this novel phosphoinositide could be important in the transduction of mitogenic and oncogenic signals.     

Inositol 1,4,5-trisphosphate activates a channel from smooth muscle sarcoplasmic reticulum

Inositol 1,4,5-trisphosphate (InsP3) can initiate calcium release into the cytoplasm in a variety of cells. From experiments using permeabilized cells, membrane vesicles, and patch-clamp techniques, it has been suggested that InsP3 acts by directly opening calcium channels. Here, we show that InsP3 induced openings of channels in planar lipid bilayers into which vesicles made from aortic muscle sarcoplasmic reticulum (SR) were incorporated. Activation of channels by InsP3 was not observed when vesicles made from SR of cardiac or skeletal muscle were incorporated into planar lipid bilayers. The present study demonstrates for the first time unique properties of an InsP3-gated calcium channel in sarcoplasmic reticulum vesicles from vascular smooth muscle. This InsP3-activated channel from aortic SR differs strikingly from the calcium-gated calcium channel of striated muscle SR in single-channel conductance and pharmacology.     

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.     

Incubation periods for paediatric AIDS patients

A recent seroprevalence study of newborns indicates that one in 62 children born in New York City has antibodies to the human immunodeficiency virus (HIV). The distribution of incubation periods for paediatric patients is needed to estimate future AIDS case loads from these seroprevalence data. Current estimates of incubation periods for paediatric patients are based on limited data. We use parametric and non-parametric methods to analyse incubation periods for 215 paediatric patients with AIDS whose only known route of infection is maternal. We conclude that incubation periods are longer than previously reported; that there is a distinct knee in the incubation period distribution at seven months which suggests two risk populations; and that there is an increase in incidence which is consistent with exponential growth.     

Visual search for a conjunction of movement and form is parallel

Treisman has proposed when a human subject performs a visual search, the search is parallel for targets defined by a single feature, and serial for targets defined by a conjunction of features. Here we report that this is not true for targets defined by a conjunction of the features movement and form. Detection of a moving X among randomly distributed moving Os and static Xs is parallel. Search is uninfluenced by the stationary stimuli despite their spatial intermingling with the moving items. Thus, attention can be restricted to a spatially dispersed perceptual group, defined by common movement. This contradicts previous conclusions from visual search experiments that attention can only be assigned to contiguous regions of visual space. The search process first segregates the array into moving and stationary items, and then examines the moving group for the target form. Cells in the middle temporal region (cortical area MT) have the properties required to perform these operations.