RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

Effect of indomethacin-treated wheat on a wild population of montane voles

Semiweekly mark and recapture livetrapping was conducted July-October 1985 to determine the effectiveness of wheat treated with inomethacin, a prostaglandin synthetase inhibitor, to control the productivity of a wild population of montane voles ( Microtus montanus ) in southeastern Idaho. Before treatment, control (C) and experimental (E) groups, each on ca 0.3 ha, were statistically equal in population size (￣X ± SD; C = 50 ± 21, E = 45 ± 14), adult female: male ratio (C = 1:0.8, E = 1:0.7), juvenile:adult ratio (C =0.16:1, E = 0.13:1), number of juveniles per 100 females (￣X ± SD; C = 27 ± 8, E = 21 ± 18), and percentage of pregnant females (￣X ± SD; C = 44 ± 10, E = 46 ± 17). After the 15-week experiment all population categories were unchanged for the control group and significantly (P ≤ .05) lower for the experimental group, which ended with a final population of (￣X ± SD) 17 ± 6, with 7 ± 21 juveniles per 100 females and an 11 ± 14% pregnancy rate.     

On Cowania and its intergeneric hybrids in Arizona

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Spawning chronology and larval emergence of June sucker ( Chasmistes liorus )

June sucker ( Chasmistes liorus ) spawned in the Provo River, Utah, over a 2-wk period in early June during both 1987 and 1988. Emergent larvae emigrated from the river to Utah Lake over a 2- to 3-wk period. Drift into the lake peaked between 1200 and 0400. During daylight hours, emergent larvae tended to occur in pools. Peak emergence of larval drift was approximately 1.2 larvae/m 3 during late June in 1987 and 1988. Recruitment failure of June sucker is not due to reproductive failure.     

Effects of watershed alteration on the brook trout population of a small Black Hills stream

The impacts of adjacent landscaping activity and livestock presence on the brook trout ( Salvelinus fontinalis ) population of a small Black Hills stream were evaluated. Moderate changes in temperature, turbidity, and fecal coliform numbers did not influence brook trout densities. Stream morphometry, particularly factors affecting stream cover, appeared to have the greatest impact on numbers of trout. Brook trout were poor indicators of moderate changes in water quality, but they were adequate indicators of the physical perturbations within the stream.      

Shorebird predation on benthic macroinvertebrates in an irrigation reservoir

American Falls Reservoir in southeastern Idaho is an irrigation reservoir used as an inland feeding stopover by many shorebird species. Six exclosure experiments were conducted during the 1990 drawdown period to investigate shorebird predation impact on benthic macroinvertebrate populations. The study sites differed in sediment composition, sediment slope, invertebrate densities, and shorebird abundance. Shorebird predation significantly affected invertebrate densities in only 1 of 6 experiments (Aberdeen Mouth). This site had higher sediment slope and a lower water recedence than other study sites, resulting in concentration of shorebird predation on a small area of newly exposed sediment. Shorebird predation had the greatest impact on medium size class chironomid larvae at Aberdeen Mouth. Our results suggest that inland sites such as American Falls Reservoir represent viable shorebird habitat and may be managed to insure consistent prey availability. Drawdown rate, sediment slope, invertebrate densities, and shorebird abundance are all important factors influencing shorebird predation. Monitoring shorebird abundance and predation impact on invertebrate densities may help in manipulating drawdown rate to provide adequate shorebird prey. Management of inland sites for shorebird use may become more important in the future as human encroachment in coastal areas continues.     

Survivorship and cause-specific mortality in five populations of mule deer

We used retrospective analyses to investigate cause-specific mortality and survivorship among 5 populations of mule deer ( N = 168 telemetered animals) wintering in the western Great Basin during 1986-1994. These populations existed under similar environmental conditions, but survivorship functions differed among them. Monthly survival ranged from 0.964 to 0.990, and annual survival ranged from 0.643 to 0.884. The proportion of deaths attributed to predation and malnutrition or anthropogenic causes did not differ among the 5 populations. Predation was the leading cause of mortality; mountain lions were responsible for approximately 90% of the deer killed by predators. No difference existed among these populations in the proportion of telemetered deer that were killed by mountain lions, but proportionally more females than males were killed by these large fields. Predation by mountain lions is the primary source of mortality and a widespread phenomenon among the populations of mule deer we investigated.     

Vernier templating and synthesis of a 12-porphyrin nano-ring

Templates are widely used to arrange molecular components so they can be covalently linked into complex molecules that are not readily accessible by classical synthetic methods. Nature uses sophisticated templates such as the ribosome, whereas chemists use simple ions or small molecules. But as we tackle the synthesis of larger targets, we require larger templates-which themselves become synthetically challenging. Here we show that Vernier complexes can solve this problem: if the number of binding sites on the template, n(T), is not a multiple of the number of binding sites on the molecular building blocks, n(B), then small templates can direct the assembly of relatively large Vernier complexes where the number of binding sites in the product, n(P), is the lowest common multiple of n(B) and n(T) (refs 8, 9). We illustrate the value of this concept for the covalent synthesis of challenging targets by using a simple six-site template to direct the synthesis of a 12-porphyrin nano-ring with a diameter of 4.7?nm, thus establishing Vernier templating as a powerful new strategy for the synthesis of large monodisperse macromolecules.     

Geochemical evidence for widespread euxinia in the later Cambrian ocean

Widespread anoxia in the ocean is frequently invoked as a primary driver of mass extinction as well as a long-term inhibitor of evolutionary radiation on early Earth. In recent biogeochemical studies it has been hypothesized that oxygen deficiency was widespread in subsurface water masses of later Cambrian oceans, possibly influencing evolutionary events during this time. Physical evidence of widespread anoxia in Cambrian oceans has remained elusive and thus its potential relationship to the palaeontological record remains largely unexplored. Here we present sulphur isotope records from six globally distributed stratigraphic sections of later Cambrian marine rocks (about 499 million years old). We find a positive sulphur isotope excursion in phase with the Steptoean Positive Carbon Isotope Excursion (SPICE), a large and rapid excursion in the marine carbon isotope record, which is thought to be indicative of a global carbon cycle perturbation. Numerical box modelling of the paired carbon sulphur isotope data indicates that these isotope shifts reflect transient increases in the burial of organic carbon and pyrite sulphur in sediments deposited under large-scale anoxic and sulphidic (euxinic) conditions. Independently, molybdenum abundances in a coeval black shale point convincingly to the transient spread of anoxia. These results identify the SPICE interval as the best characterized ocean anoxic event in the pre-Mesozoic ocean and an extreme example of oxygen deficiency in the later Cambrian ocean. Thus, a redox structure similar to those in Proterozoic oceans may have persisted or returned in the oceans of the early Phanerozoic eon. Indeed, the environmental challenges presented by widespread anoxia may have been a prevalent if not dominant influence on animal evolution in Cambrian oceans.