No abstract

Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.

Herpes simplex keratitis (HSK) is an inflammatory response to viral infection and self antigens in the cornea and is a major cause of blindness. Using two strains of mice which are susceptible (129/SVEV) and resistant (C57BL/6) to herpes simplex virus (HSV) strain KOS, (129/SVEV × C57BL/6)F2 mice were generated and examined for their disease susceptibility in terms of clinical symptoms, ocular disease, and antibody production following corneal scarification with HSV (KOS). A genome-wide screen was carried out using microsatellite markers to determine the genetic loci involved in this response. Loci on chromosomes 4, 5, 12, 13, and 14 were shown to be involved in general susceptibility to clinical disease, whereas loci on chromosomes 10 and 17 were shown to be unique to ocular disease

Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to < 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.

Nano-and micron-sized metal particles have important applications in catalysis and in the medical and electronic industries. For applications requiring high conductivity, such as thick film conductive pastes or isotropic conductive adhesives, AgCu particles combine high conductivity with advantages of lower costs. Here, we report the generation of AgCu particles by spray pyrolysis, a process that has the advantages of simple experimental setup, large-scale production ability, and controllable particle size. Solutions of copper nitrate and silver nitrate dissolved in deionized water with either 40 vol% ethanol (ET) or 40 vol% ethylene glycol (EG) were used as the precursor. Phase separation was observed during the generation of AgCu particles, and the particles were mainly Ag-rich and Cu-rich solid solutions. The short reactor residence time experiments indicated that both the cosolvent properties and operating conditions affect the particle formation process and change the structure of particles.