Methyllycaconitine,a naturally occurring insecticide with a high affinity for the insect cholinergic receptor

Summary Studies of extracts ofDelphinium seeds, long known to be insecticidal, revealed that a principal insecticidal toxin was methyllycaconitine, which is shown to be a potent inhibitor of -bungarotoxin binding to housefly heads (K_inh=2.5×10^–10±0.5×10^–10M).Calgary for gifts of MLA, citrate and lycoctonine, and Dr W. Bowers of the University of Arizona for the original extract ofDelphinium seeds. We would also like to acknowledge the able technical support of Ms C. Dushin, Mr E.L. Bowman, Dr C. C. Gagne, Mr R. F. Borysewicz and Dr P. Mowery for his assistance in obtaining and interpreting the carbon-13 NMR spectra.     

A rare variant in CFH directly links age-related macular degeneration with rare glomerular nephropathies

A careful analysis of risk haplotypes in relation to age-related macular degeneration (AMD) susceptibility has led to the identification of a rare, high-penetrance variant in the complement factor H (CFH) gene that is also causally associated with atypical hemolytic uremic syndrome (aHUS) and related glomerulopathies. This finding provides a convincing causal mechanism linking the two diseases and develops a paradigm for the genetic architecture of a common and complex disease.     

The worldwide leaf economics spectrum

Bringing together leaf trait data spanning 2,548 species and 175 sites we describe, for the first time at global scale, a universal spectrum of leaf economics consisting of key chemical, structural and physiological properties. The spectrum runs from quick to slow return on investments of nutrients and dry mass in leaves, and operates largely independently of growth form, plant functional type or biome. Categories along the spectrum would, in general, describe leaf economic variation at the global scale better than plant functional types, because functional types overlap substantially in their leaf traits. Overall, modulation of leaf traits and trait relationships by climate is surprisingly modest, although some striking and significant patterns can be seen. Reliable quantification of the leaf economics spectrum and its interaction with climate will prove valuable for modelling nutrient fluxes and vegetation boundaries under changing land-use and climate.     

Chitotriosidase and gene therapy for fungal infections

Chitotriosidase secreted by activated human macrophages has been implicated in the defence against chitin-bearing pathogens. The antifungal properties of human chitotriosidase were investigated here following retroviral vector-mediated gene transfer of the open reading frame of the chitotriosidase gene into Chinese hamster ovary cells. A chitinase assay confirmed that the engineered cells secreted recombinant chitotriosidase constitutively. Two dimensional gel electrophoresis and western blotting indicated that the recombinant protein is the major, chitin-binding, fifty kilodalton isoform. Culture medium conditioned by the transduced cells inhibited growth of isolates of Aspergillus niger, Candida albicans and Cryptococcus neoformans. Furthermore, longevity was significantly increased in a mouse model of cryptococcosis when cells transduced with the chitotriosidase gene and encapsulated in alginate microspheres were implanted subcutaneously in the animals. Engraftment of microcapsules containing cells transduced with the chitotriosidase gene has the potential to combat infections caused by chitinous pathogens through the prolonged delivery of recombinant chitotriosidase. Received 29 November 2008; received after revision 11 January 2009; accepted 13 January 2009     

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1?3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.     

Mutations in CEP57 cause mosaic variegated aneuploidy syndrome

Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division.     

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.