Generation of prion transmission barriers by mutational control of amyloid conformations

Self-propagating beta-sheet-rich protein aggregates are implicated in a wide range of protein-misfolding phenomena, including amyloid diseases and prion-based inheritance. Two properties have emerged as common features of amyloids. Amyloid formation is ubiquitous: many unrelated proteins form such aggregates and even a single polypeptide can misfold into multiple forms--a process that is thought to underlie prion strain variation. Despite this promiscuity, amyloid propagation can be highly sequence specific: amyloid fibres often fail to catalyse the aggregation of other amyloidogenic proteins. In prions, this specificity leads to barriers that limit transmission between species. Using the yeast prion [PSI+], we show in vitro that point mutations in Sup35p, the protein determinant of [PSI+], alter the range of 'infectious' conformations, which in turn changes amyloid seeding specificity. We generate a new transmission barrier in vivo by using these mutations to specifically disfavour subsets of prion strains. The ability of mutations to alter the conformations of amyloid states without preventing amyloid formation altogether provides a general mechanism for the generation of prion transmission barriers and may help to explain how mutations alter toxicity in conformational diseases.     

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.     

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.     

Opportunities for new research using the post-2001 ONS Longitudinal Study

The addition of 2001 Census data to the ONS Longitudinal Study extends the range of research topics that this unique data resource can support. Census questions on religion, care-giving and self-rated health that were asked for the first time in 2001 and the repetition of 1991 questions on limiting long-standing illness and ethnicity raise opportunities for new longitudinal investigation in these areas. This article describes how new 2001 methodologies including data imputation, the One Number Census and de jure enumeration affect the LS database. The support service for existing and prospective LS users is described.     

The selective accumulation of vitellogenin in the locust oocyte

Summary The selectivity of vitellogenin absorption by the locust oocyte was examined by comparing the uptake of vitellogenin and a haemolymph protein of similar molecular weight (MHP). Though both proteins occurred in the haemolymph at approximately the same concentration there occurred a 500-fold difference in accumulation of vitellogenin over MHP during a 24-h period. Surprisingly MHP did not accumulate in the oocyte during vitellogenesis.     

Gamma globulins in the mice vaginal fluids: Cyclic and experimental variations

Summary The study of the gamma globulins in the vaginal fluids reveals that the lowest values were found in mice at estrus and in castrated mice 8 days after the estrogen treatment. We suggest that the variation of gamma globulins in the vaginal fluids is influenced both under physiological and experimental conditions by estrogens.This work was supported by a grant of the Conicet No. 4973 b/74.Fellow of Scientific Investigator Career. Consejo Nacional de Investigaciones Cientificas y Técnicas.Member of Scientific Investigator Career. Consejo Nacional de Investigaciones Científicas y Técnicas.     

Biodiversity (Communications arising): maize transgene results in Mexico are artefacts

Quist and Chapela's conclusion that the transgenes they claim to have detected in native maize in Oaxaca, Mexico, are predominantly reassorted and inserted into a "diversity of genomic contexts" seems to be based on an artefact arising from the inverse polymerase chain reaction (i-PCR) they used to amplify sequences flanking 35S transgenes from cauliflower mosaic virus (CaMV).     

Growth and demography of one population of the lizard Sceloporus mucronatus mucronatus

We report on growth and demography of Sceloporus mucronatus mucronatus , a lizard subspecies endemic to central Mexico. We characterize the life history of this subspecies, provide quantitative information relevant to conservation, and add to the growing literature on the diversity of life histories in the genus Sceloporus . We calculated body growth rates and fitted them to the Von Bertalanffy, the logistic-by-length, and the logistic-by-weight growth models. The Von Bertalanffy model provided the best fit, and we used it to analyze the growth pattern. Growth rates were similar during the 1st year of life in both sexes, but after that point males grew faster and reached maturity earlier (20 months) than females (31 months). We used a population projection matrix to model population dynamics during 2003–2004 and found a positive population growth rate (λ = 1.769). However, based on the projected stable size-class vector ( w ), this population does not appear to have reached stability, and it might be currently experiencing considerable interannual fluctuations. Elasticity values showed that the transition from the juvenile stage to the 1st adult stage was the vital rate that contributes the most to population growth rate, followed by fecundity and stasis of the 1st reproductive category. While total elasticities for demographic processes were similar, elasticities per size class showed the relatively high importance of small adults in comparison to juveniles and large adults. The restriction of this endemic subspecies to central Mexico, where human activities and consequent habitat destruction are increasing, demands further quantitative evaluation and monitoring of populations, even though our results indicate a potential for population growth.