The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans

More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.     

Wnt-beta-catenin signaling initiates taste papilla development

Fungiform taste papillae form a regular array on the dorsal tongue. Taste buds arise from papilla epithelium and, unusually for epithelial derivatives, synapse with neurons, release neurotransmitters and generate receptor and action potentials. Despite the importance of taste as one of our five senses, genetic analyses of taste papilla and bud development are lacking. We demonstrate that Wnt-beta-catenin signaling is activated in developing fungiform placodes and taste bud cells. A dominant stabilizing mutation of epithelial beta-catenin causes massive overproduction of enlarged fungiform papillae and taste buds. Likewise, genetic deletion of epithelial beta-catenin or inhibition of Wnt-beta-catenin signaling by ectopic dickkopf1 (Dkk1) blocks initiation of fungiform papilla morphogenesis. Ectopic papillae are innervated in the stabilizing beta-catenin mutant, whereas ectopic Dkk1 causes absence of lingual epithelial innervation. Thus, Wnt-beta-catenin signaling is critical for fungiform papilla and taste bud development. Altered regulation of this pathway may underlie evolutionary changes in taste papilla patterning.     

The Social Network Analysis of Techno-Economic Systems:Comparing Results Based on Binary and Weighted Networks

The network analysis of a technological system combines the interindustry transactions with a matrix of sectoral innovative efforts as measured by R&D investment intensity.The matrixes of interindustry transactions of R&D-embodied products(innovations)are weighted matrixes where the interindustry flows measure the intensity of the innovation diffusion.In the past,studies using this approach in innovation studies have transformed weighted matrixes into binary matrixes of zero and one element where the flows less than a selected threshold value were considered to be zero and the flows greater than the threshold value were counted as one.Such matrix transformation leads to the loss of a great deal of information.In the present study,using degree and clustering coefficients for both binary direct as well as weighted direct techno-economic networks of the manufacturing sector of the German economy,we show that the binary directed network analysis is incapable of refined ranking of interindustry innovation transactions.The total degree index based on the weighted network of the German techno-economic system assigns a unique ranking to each sector,and clustering coefficients show that at least 75%of sectors in the network of Germany have two links with the other industries.However,the same indices based on the binary network are incapable of such refined ranking.     

ASYMPTOTIC NORMALITY OF SOME ESTIMATORS IN A FIXED-DESIGN SEMIPARAMETRIC REGRESSION MODEL WITH LINEAR TIME SERIES ERRORS

Consider a semiparametric regression model with linear time series errors Yk = x'kβ g(tk) εk, 1 < k < n, where Yk's are responses, xk = (xk1,xk2,..... ,xkp)' and tk ∈T ∪R are fixed design points, β= (β1, β2, ....., βp)' is an unknown parameter vector, g(.) is an unknown bounded real-valued function defined on a compact subset T of the real line R, and εk is a linear process given by εk = ∑j=0∞j(?)ek-j,(?)= 1, where , are i.i.d. random variables. In this paper we establish the asymptotic normality of the least squares estimator of β, a smooth estimator of g(.), and estimators of the autocovariance and autocorrelation functions of the linear process εk.     

Estimates of true birth order for Scotland, 1945-1999

Over the last three decades fertility in Scotland, as measured by the total fertility rate (TFR), has moved from being higher than in England and Wales, to being lower. The annual number of births in Scotland has declined so that in the mid-1990s low fertility became the main driver of the overall population decline that Scotland has been experiencing since 1974. Analysis of fertility by birth order is instrumental in gaining an understanding of past and future fertility trends. Until the rise in births outside marriage in the 1980s data from registration could be used as a proxy for true birth order. However, because birth order is not collected for births outside marriage true birth order now has to be estimated. This article presents the first official estimates of true birth order for Scotland. The construction of these estimates based on a modified version of the method used for England and Wales is discussed. This article also presents analysis relating births by true birth order estimate to the population of women by parity on a cohort basis, and makes comparisons with England and Wales.     

Family building intentions in England and Wales: trends,outcomes and interpretations

This article presents and analyses women's childbearing intentions collected in the General Household Survey (GHS). Data from the 21 surveys from 1979 to 2001 show that over that period there has been a fall in women's intended numbers of births. However the latest data (from the 1998, 2000 and 2001 surveys) show that the average number of children intended is still around two, somewhat higher than the average number of children current fertility rates suggest women will have. The questions of whether this difference can be interpreted as possible unmet need for children, whether past intentions have been good predictors of fertility, and how current intentions may be used to inform projections assumptions are discussed. In relation to the last question, fertility intentions by ethnic group are also presented.     

Which authorities are alike?

This article describes the first results from the recent revision to The ONS classification of local and health authorities of Great Britain to allow for boundary changes. For each local and health authority of Great Britain as at April 1999 it presents 'most similar' authorities as measured by a selection of 37 socioeconomic and demographic variables from the 1991 Census. These results will assist local and health authorities in identifying other appropriate authorities for comparative studies. A second article, to be published in Population Trends 99, will present the results of the analysis to identify groups of authorities in a hierarchy of new Clusters, Groups and Families for the revised classification.