Osteoclast differentiation and activation

Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.     

Macroinvertebrate community structure and related environmental variables in two forks of the Virgin River, Utah

Using multivariate analysis techniques, we analyzed variation in the structure of the benthic macroinvertebrate community in the North Fork and East Fork of the Virgin River in and above Zion National Park in concert with a number of naturally occurring and anthropogenic environmental variables. Correspondence analysis revealed that the community structure in the 2 streams was markedly different despite occurring in areas similar in topography, elevation, and terrestrial vegetation cover. Subsequent analyses of the 2 streams separately using canonical correspondence analysis to test for strength of association of environmental variables with variations in benthic macroinvertebrate community structure revealed that communities in the East Fork of the Virgin River were more associated with nitrogen-related variables influenced by agricultural and urban activities along the river and that communities in the North Fork were most strongly associated with naturally occurring physical variables.     

Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene

The fibrinolytic potential of the vasculature is modulated primarily by the availability and activity of plasminogen activators, which convert the zymogen plasminogen into the active fibrin-degrading enzyme plasmin. The activities of these key regulatory enzymes are directly neutralized by their primary endogenous inhibitor, plasminogen activator inhibitor-1 (PAI-1). Although some individuals with a tendency to develop thrombotic disorders exhibit elevated levels of PAI-1 in their plasma, the cause-and-effect relationship between increased PAI-1 and thrombosis is still unclear. Specifically, it is not known whether chronic depression of fibrinolytic activity results in the development of thrombosis. To address this question we developed transgenic mice in which the contribution of PAI-1 to thrombus formation could be evaluated. The results presented in this report indicate that elevated levels of PAI-1 contribute to the development of venous but not arterial occlusions.     

Thymine dimer repair in fibroblasts of patients with dysplastic naevus syndrome (DNS)

Dysplastic naevus syndrome (DNS) is frequently observed in association with familial melanoma and xeroderma pigmentosum (XP), but the role of UV-light in the development of DNS has not been elucidated. Previous work has shown that UV-induced unscheduled DNA synthesis is associated with the early loss of antigenicity observed in immunoassays using a monoclonal antibody specific for thymine-thymine dimers. We now show that the rate of loss of antigenicity, which reflects the relative amount of bound antibody, observed during the first 60 min following 10 Jm-2 UVC irradiation is significantly reduced (p = 0.02) in cultures of fibroblasts from 7 out of 8 DNS patients compared with the results from cells of a group of 30 healthy volunteers. This observation suggests an early event in excision repair is altered in the majority of DNS patients.     

The creation of 'consistent areas through time' (CATTs) in Scotland, 1981-2001

Small area analysis of sociodemographic change over time is often impeded by the changing configuration of census zones for each decennial UK census. Approaches for matching zone configurations exist, but these typically require population estimation techniques, which inevitably involve some error. Because of the postcode-based geographical zoning system used in Scottish censuses, it is possible to create a local-area geography which is consistent for recent censuses. Here we present a methodology used to create three sets of consistent areas through time (CATTs) that can be used for analysing comparable small area data output from the 1981, 1991 and 2001 Censuses.     

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.     

Functional identification of an aggression locus in the mouse hypothalamus

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.