Effect of heterogeneity on the chromosome 10 risk in late-onset Alzheimer disease

Communicated by Christine Van Broeckhoven With the exception of ApoE (APOE), no universally accepted genetic association has been identified with lateonset Alzheimer disease (AD). A broad region of chromosome 10 has engendered continued interest generated from both preliminary genetic linkage and candidate gene studies. To better examine this region, we combined unbiased genetic linkage with candidate gene association studies. We genotyped 36 SNPs evenly spaced across 80.2 Mb in a family-based data set containing 1,337 discordant sibling pairs in 567 multiplex families to narrow the peak region of linkage using both covariate and subset analyses. Simultaneously, we examined five functional candidate genes (VR22, LRRTM3, PLAU, TNFRSF6, and IDE) that also fell within the broad area of linkage. A total of 50 SNPs were genotyped across the genes in the family-based data set and an independent case-control data set containing 483 cases and 879 controls. Of the 50 SNPs in the five candidate genes, 22 gave nominally significant association results in at least one data set, with at least one positive SNP in each gene. SNPs rs2441718 and rs2456737 in VR22 (67.8 Mb) showed association in both family-based and case-control data sets (both P 5 0.03). A two-point logarithmic odds (LOD) score of 2.69 was obtained at SNP rs1890739 (45.1 Mb, P 5 0.03 in 21% of the families) when the families were ordered from low to high by ApoE LOD score using ordered subset analysis (OSA). These data continue to support a role for chromosome 10 loci in AD. However, the candidate gene and linkage analysis results did not converge, suggesting that there is more extensive heterogeneity on chromosome 10 than previously appreciated. Hu

Moving in the anthropocene: global reductions in terrestrial mammalian movements

Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission

The Synthetic-Technical Development of Oseltamivir Phosphate Tamiflu™: A Race against Time

The clinical development of the first orally available neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu™) proceeded very fast. In order to support this program an unprecedented team effort in chemical process research, development, piloting, production and analytics took place, which allowed the successful launch of Tamiflu™ in 1999, only two and a half years after it was licensed from Gilead Sciences. This article describes selected aspects of the commercially used synthesis route and a brief summary of alternative syntheses devised by Roche chemists

Linkage and association analysis of chromosome 19q13 in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune neurological disorder with a complex etiology. Sibling risk, twin, and adoption studies have demonstrated that genes play a vital role in susceptibility to MS. Numerous association and linkage studies have implicated the major histocompatibility complex (MHC) as one component of the genetic etiology, but additional loci remain to be identified. Genomic screens have suggested over 50 regions that might harbor these genes, but there has been little agreement between studies. The one region suggested by all four screens resides within chromosome 19q13. Allelic associations with several markers in this region have also been described. This region has now been examined in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and non-parametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appears to be modest with a maximum λS=1.47, probably representing no more than 10% of the overall genetic effect in MS

Effect of precipitation change and functional identity on decomposition of <i>Holcus mollis</i> at different time points.

<p>Decomposition of <i>H. mollis</i> litter in 2009 for all fourteen treatments. a) Dec–Mar F_1,49 = 32.87, p<0.001, b) Dec–Jun F_1,49 = 40.23, p<0.001, c) Dec–Sept F_1,49 = 20.31, p<0.001. Error bars represent ±1 SEM.</p

Total seasonal rainfall inputs throughout the experiment.

<p>Total seasonal rainfall inputs throughout the experiment.</p

Results of linear mixed effects models testing precipitation change (PC) and functional group (FG) treatment effects upon vegetation cover and species richness.

<p>Results of linear mixed effects models testing precipitation change (PC) and functional group (FG) treatment effects upon vegetation cover and species richness.</p

Effect of precipitation change and functional identity on ecosystem respiration at different time points.

<p>The response of ecosystem respiration to precipitation change (PC) and functional group (FG) identity at six time points through the experiment. a) May 2009 (presence/absence of FG1 F_1,42 = 4.72, p = 0.036, interaction between FG2 and FG3, F_1,42 = 5.031, p = 0.03), b) September 2009 (PC F_1,42 = 4.596, p = 0.038), c) November 2009, (interaction between PC and FG3 F_1,42 = 7.165, p = 0.010), d) February 2010 (FG1, F_1,45 = 4.521_, p = 0.039), e) June 2010 (interaction between PC and FG1, F_1,45 = 5.80, p = 0.020) f) August 2010 (interaction between PC and FG1 F_1,45 = 6.46, p = 0.015).</p