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.     

Common deletion polymorphisms in the human genome

The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies.     

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.     

Butterflies (Lepidoptera: Papilionoidea) of Mount Kilimanjaro: Nymphalidae subfamilies Libytheinae,Danainae, Satyrinae and Charaxinae

This paper, which presents an annotated checklist of the ‘lower Nymphalidae’ (Libytheinae, Danainae, Satyrinae, Charaxinae), is the fourth in a series on the butterfly fauna of Mount Kilimanjaro. Four genera of lower Nymphalidae (Danaus, Amauris, Bicyclus, Charaxes), with a total of 11 included species, are known or believed to occur within the main forest zone, from c. 1800 to 2800 m. Of these, only three species of Charaxes (Charaxes berkeleyi, Charaxes ansorgei, Charaxes xiphares) may be restricted locally to this primary forest. The lower slopes fauna, below 1800 m, is considerably richer, with a total of 11 genera and 41 species listed (8 species of which extend into the forest zone). Possible additional species, dubious earlier records, problems with African subspecies of Danaus chrysippus, a need for more work on certain Satyrinae, and classification of the genus Charaxes are discussed. An identification key to the subfamilies of Nymphalidae, and the 19 genera of Libytheinae, Danainae, Satyrinae, Charaxinae that occur in Tanzania, together with a key to the adults of all the species of these four subfamilies considered to occur or have occurred on Kilimanjaro, with 206 colour images, are included as online Supplementary Information.     

Empirical factors and structure transference: Returning to the London account

We offer a framework to represent the roles of empirical and theoretical factors in theory construction, and examine a case study to illustrate how the framework can be used to illuminate central features of scientific reasoning. The case study provides an extension of French and Ladyman's (1997) analysis of Fritz and Heinz London's model of superconductivity to accommodate the role of the analogy between superconductivity and diamagnetic phenomena in the development of the model between 1935 and 1937. We focus on this case since it allows us to separate the roles of empirical and theoretical factors, and so provides an example of the utility of the approach that we have adopted. We conclude the paper by drawing on the particular framework here developed to address a range of concerns.