Converging lines of evidence implicate the beta-amyloid peptide (Ab) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Ab production by functionally inhibiting g-secretase, the activity responsible for the carboxy-terminal cleavage required for Ab production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Ab production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-di¯uoro-phenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP V717F reduces brain levels of Ab in a dose-dependent manner within 3 h. These studies represent the ®rst demonstration of a reduction of brain Ab in vivo. Development of such novel functional g-secretase inhibitors will enable a clinical examination of the Ab hypothesis that Ab peptide drives the neuropathology observed in Alzheimer's disease.

Demographic data show many populations of Rocky Mountain (Cervus elaphus nelsoni) and Roosevelt (Cervus elaphus roosevelti) elk have been declining over the last few decades. Recent work suggests that forage quality and associated animal nutritional condition, particularly in late summer and early autumn, influence reproduction and survival in elk. Therefore, we estimated seasonal nutritional condition of 861 female elk in 2,114 capture events from 21 herds in Washington, Oregon, Wyoming, Colorado, and South Dakota from 1998 to 2007. We estimated ingesta-free body fat and body mass, and determined age, pregnancy status, and lactation status. We obtained estimates for most herds in both late winter-early spring (late Feb-early Apr) and in autumn (Nov-early Dec) to identify changes in nutritional condition of individuals across seasons.Body fat levels of lactating females in autumn were consistently lower than their non-lactating counterparts, and herd averages of lactating elk ranged from 5.5% to 12.4%. These levels were 30-75% of those documented for captive lactating elk fed high-quality diets during summer and autumn. Body fat levels were generally lowest in the coastal and inland northwest regions and highest along the west-slope of the northern Cascades. Adult females in most herds lost an average of 30.7 kg (range: 5-62 kg), or about 13% (range: 2.6-25%) of their autumn mass during winter, indicating nutritional deficiencies. However, we found no significant relationships between spring body fat or change in body fat over winter with winter weather, region, or herd, despite markedly different winter weather among herds and regions. Instead, body fat levels in spring were primarily a function of fat levels the previous autumn. Thinner females in autumn lost less body fat and body mass over winter than did fatter females, a compensatory response, but still ended the season with less body fat than the fatter elk.Body fat levels of lactating females in autumn varied among herds but were unrelated to their body fat levels the previous spring. Within herds, thinner females exhibited a compensatory response during summer and accrued more fat than their fatter counterparts over summer, resulting in similar body fat levels among lactating elk in autumn despite considerable differences in their fat levels the previous spring. Level of body fat achieved by lactating females in autumn varied 2-fold among herds, undoubtedly because of differences in summer nutrition. Thus, summer nutrition set limits to rates of body fat accrual of lactating females that in turn limited body condition across the annual cycle.Pregnancy rates of 2-to 14-year-old females ranged from 68% to 100% in coastal populations of Washington, 69% to 98% in Cascade populations of Washington and Oregon, 84% to 94% in inland northwestern populations of Washington and Oregon, and 78% to 93% in Rocky Mountain populations. We found evidence of late breeding, even in herds with comparatively high pregnancy rates. Mean body mass of calves (n ¼ 242) in 3 popul...

The carbon-isotope composition of hair and feces offers a glimpse into the diets of mammalian herbivores. It is particularly useful for determining the relative consumption of browse and graze in tropical environments, as these foods have strongly divergent carbon-isotope compositions. Fecal δ13C values reflect the last few days consumption, whereas hair provides longer term dietary information. Previous studies have shown, however, that some fractionation occurs between dietary δ13C values and those of hair and feces. Accurate dietary reconstruction requires an understanding of these fractionations, but few controlled-feeding studies have been undertaken to investigate these fractionations in any mammalian taxa, fewer still in large mammalian herbivores. Here, we present data from the first study of carbon-isotope fractionation between diet, hair, and feces in multiple herbivore taxa. All taxa were fed pure alfalfa (Medicago sativa) diets for a minimum period of 6 months, at which point recently grown hair was shaved and analyzed for carbon isotopes. The mean observed diet–hair fractionation was +3.2‰, with a range of +2.7 to +3.5‰. We also examined diet–feces fractionation for herbivores on alfalfa and bermudagrass (Cynodon dactylon) feeds. The mean diet–feces fractionation for both diets was –0.8‰, with less fractionation for alfalfa (–0.6‰) than bermudagrass (–1.0‰). Fecal carbon turnover also varies greatly between taxa. When diets were switched, horse (Equus caballus) feces reflected the new diet within 60 h, but alpaca (Lama pacos) feces did not equilibrate with the new diet for nearly 200 h. Thus, fecal carbon isotopes provide far greater dietary resolution for hindgut-fermenting horses than foregut-fermenting alpacas.

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Type II functional responses are frequently observed in herbivores feeding in patches where plants are concentrated in space. We tested a mechanistic model of regulation of intake rate of herbivores foraging in food-concentrated patches (Laca and Demment 1992, Spalinger and Hobbs 1992) that accounts for asymptotic, Type II responses. The model is based on the hypothesis that competition between cropping and chewing regulates instantaneous intake rate in response to changes in the size of bites obtained by the forager. We tested this hypothesis and examined the ability of our model to account for observations of intake rate of 12 species of mammalian herbivores ranging in body mass over 4 orders of magnitude.We measured short-term intake rates of mammalian herbivores feeding in hand-assembled patches of plants. We varied bite size by changing plant height and density in patches offered to herbivores, and observed dry matter intake rates in response to this variation. Averaged across species, our model accounted for 77% of the variance in food intake rate (P < .001 for all species). Predictions of maximum intake rate closely resembled observations of processing capacity, demonstrating that processing rather than cropping sets an upper limit on short-term intake. Tests of model mechanisms provided strong support for the hypothesis that competition between cropping and chewing is responsible for the Type II functional response seen in herbivores feeding in food-concentrated patches. The model was able to consistently predict intake rates observed in 16 previous studies. These results indicate that plant characteristics regulating bite size (e.g., leaf size and geometry, spinescence) frequently control instantaneous rates offood intake by mammalian herbivores.