Prion propagation and toxicity in vivo occur in two distinct mechanistic phases

Mammalian prions cause fatal neurodegenerative conditions including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. Prion infections are typically associated with remarkably prolonged but highly consistent incubation periods followed by a rapid clinical phase. The relationship between prion propagation, generation of neurotoxic species and clinical onset has remained obscure. Prion incubation periods in experimental animals are known to vary inversely with expression level of cellular prion protein. Here we demonstrate that prion propagation in brain proceeds via two distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration which rapidly reaches a maximal prion titre, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrate an uncoupling of infectivity and toxicity. We suggest that prions themselves are not neurotoxic but catalyse the formation of such species from PrP(C). Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.     

A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.     

Leukocyte mobilization from the guinea pig spleen by muscarinic cholinergic stimulation

Important interactions between the immune system and the nervous and endocrine systems have become increasingly accepted. The present results demonstrate that the cholinergic agonist carbacholine greatly increased the number of granulocytes and lymphocytes in the splenic venous blood, but not arterial blood, shortly after administration to guinea pigs. The effect was largely blocked by pretreatment with atropine. In contrast, animals treated with indomethacin had a decreased number of leukocytes in both splenic venous and arterial blood. A decrease in relative splenic weight due to carbacholine treatment was also blocked by atropine. However, cholinergic leukocyte mobilization, or that previously observed after adrenergic stimulation, may not be caused by capsule contraction since it is not accompanied by mobilization of erythrocytes. Furthermore, indomethacin, which potentiates the response of splenic smooth muscle to adrenergic stimuli, blocked the effect of noradrenaline (NA) on leukocyte mobilization.     

The diet of Australopithecus sediba

Specimens of Australopithecus sediba from the site of Malapa, South Africa (dating from approximately 2 million years (Myr) ago) present a mix of primitive and derived traits that align the taxon with other Australopithecus species and with early Homo. Although much of the available cranial and postcranial material of Au. sediba has been described, its feeding ecology has not been investigated. Here we present results from the first extraction of plant phytoliths from dental calculus of an early hominin. We also consider stable carbon isotope and dental microwear texture data for Au. sediba in light of new palaeoenvironmental evidence. The two individuals examined consumed an almost exclusive C(3) diet that probably included harder foods, and both dicotyledons (for example, tree leaves, fruits, wood and bark) and monocotyledons (for example, grasses and sedges). Like Ardipithecus ramidus (approximately 4.4 Myr ago) and modern savanna chimpanzees, Au. sediba consumed C(3) foods in preference to widely available C(4) resources. The inferred consumption of C(3) monocotyledons, and wood or bark, increases the known variety of early hominin foods. The overall dietary pattern of these two individuals contrasts with available data for other hominins in the region and elsewhere.     

A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa.

Mutations within the rhodopsin gene are known to give rise to autosomal dominant retinitis pigmentosa (RP), a common hereditary form of retinal degeneration. We now describe a patient with autosomal recessive RP who is homozygous for a nonsense mutation at codon 249 within exon 4 of the rhodopsin gene. This null mutation, the first gene defect identified in autosomal recessive retinitis pigmentosa, should result in a functionally inactive rhodopsin protein that is missing the sixth and seventh transmembrane domains including the 11-cis-retinal attachment site. We also found a different null mutation carried heterozygously by an unrelated unaffected individual. Heterozygous carriers of either mutation had normal ophthalmologic examinations but their electroretinograms revealed an abnormality in rod photoreceptor function.     

Drumming behavior and life history notes of a high-altitude Colorado population of the stonefly Isoperla petersoni Needham

Late instar nymphs and adults of a Colorado Hudsonian zone population of Isoperla petersoni Needham and Christenson were studied during the summer and early fall months of 1998, when stream temperature ranged from 3.3° C to 8.9° C. Early and middle instar nymphs were absent from July to October, and nymphs attained maximum size in mid-August during the 2nd week of adult field presence, suggesting a univoltine-slow life cycle. Nymphs were carnivorous and fed primarily on chironomid larvae. Adults were present from August to mid-October, with peak numbers of adult males and females occurring in mid-September and late September, respectively. Fecundity of field-collected females averaged 94.1 ± 45.15 eggs per female in September ( N = 81) and decreased to 85.2 ± 57.6 in October ( N = 12). Drumming duets were 2-way (male-female), and female answers followed male calls (nonoverlapped) or began before completion of the male call (overlapped). Male calls averaged 11.1 ± 2.09 beats and female answers averaged 6.2 ± 2.99, with mean intervals of 118 and 58 ms, respectively. The average number of female answer beats increased from 5.3 ± 2.56 when duets were nonoverlapped, to 6.6 ± 3.08 when overlapped.