Influence of Tree Species and Size on Bark Browsing by Large Wild Herbivores.

Although an important part of the ecosystem, large wild herbivores (LWH), especially red deer (Cervus elaphus L.), cause significant damage to economically valuable timber in forests of Central Europe. Recent work has demonstrated that less valuable softwood broadleaved trees can act as "biological control" that helps reduce bark browsing on more valuable trees in a mixed stand. To better understand the factors that influence how much bark area and mass are removed by LWH from these broadleaved trees, we took advantage of a novel "natural" experiment that occurred after a breach in a herbivory exclosure surrounding a 10-year old mixed broadleaved/conifer stand in the Western Carpathians in north-western Slovakia. We measured the area of old (up to 2 years previously) and new browsed patches on stems of common aspen (Populus tremula L.), common rowan (Sorbus aucuparia L.) and goat willow (Salix caprea L.), and their position along the vertical profile of the stem. The browsed bark area (cm2) was then converted to the bark mass (g) removed and the proportion of browsed bark to total bark (%) using conversion equations. Our models demonstrated that the amount of bark removed was influenced by tree species, stem diameter, age of browsing (old vs. new), and stem section along the vertical profile. LWH removed the most bark area from willow but the most bark mass from aspen because aspen had thicker bark than the other tree species. Bark browsing was greater on trees > 6 cm basal diameter. The distribution of bark browsing along the vertical profile was symmetrical (unimodal) with maximum intensity at 101−125 cm from the ground, which corresponds with the height most optimal for feeding by red deer. However, previous browsing in 2019 and 2020 caused new browsing on willow in 2021 to be focused in stem sections lower (51−75 cm) and higher (126−150 cm) than that optima. By quantifying browsing patterns and the amount of bark that is accessible to LWH for forage on the most attractive softwood broadleaved trees, our work will contribute to developing better methods for protecting commercially important species such as European beech (Fagus sylvatica L.) and Norway spruce (Picea abies L. Karst.) in areas of Central Europe that are greatly affected by increasing population density of LWH, especially red deer.

Food quality, security, and thermal refuge influence the use of microsites and patches by pygmy rabbits (Brachylagus idahoensis) across landscapes and seasons.

How intensely animals use habitat features depends on their functional properties (i.e., how the feature influences fitness) and the spatial and temporal scale considered. For herbivores, habitat use is expected to reflect the competing risks of starvation, predation, and thermal stress, but the relative influence of each functional property is expected to vary in space and time. We examined how a dietary and habitat specialist, the pygmy rabbit (Brachylagus idahoensis), used these functional properties of its sagebrush habitat-food quality, security, and thermal refuge-at two hierarchical spatial scales (microsite and patch) across two seasons (winter and summer). At the microsite and patch scales, we determined which plant functional traits predicted the number of bites (i.e., foraging) by pygmy rabbits and the number of their fecal pellets (i.e., general habitat use). Pygmy rabbits used microsites and patches more intensely that had higher crude protein and aerial concealment cover and were closer to burrows. Food quality was more influential when rabbits used microsites within patches. Security was more influential in winter than summer, and more at Cedar Gulch than Camas. However, the influence of functional properties depended on phytochemical and structural properties of sagebrush and was not spatiotemporally consistent. These results show function-dependent habitat use that varied according to specific activities by a central-place browsing herbivore. Making spatially explicit predictions of the relative value of habitat features that influence different types of habitat use (i.e., foraging, hiding, and thermoregulating) will improve how we predict patterns of habitat use by herbivores and how we monitor and manage functional traits within habitats for wildlife.

Facial and Vocal Markers of Schizophrenia Measured Using Remote Smartphone Assessments: Observational Study.

BACKGROUND: Machine learning-based facial and vocal measurements have demonstrated relationships with schizophrenia diagnosis and severity. Demonstrating utility and validity of remote and automated assessments conducted outside of controlled experimental or clinical settings can facilitate scaling such measurement tools to aid in risk assessment and tracking of treatment response in populations that are difficult to engage. OBJECTIVE: This study aimed to determine the accuracy of machine learning-based facial and vocal measurements acquired through automated assessments conducted remotely through smartphones. METHODS: Measurements of facial and vocal characteristics including facial expressivity, vocal acoustics, and speech prevalence were assessed in 20 patients with schizophrenia over the course of 2 weeks in response to two classes of prompts previously utilized in experimental laboratory assessments: evoked prompts, where subjects are guided to produce specific facial expressions and speech; and spontaneous prompts, where subjects are presented stimuli in the form of emotionally evocative imagery and asked to freely respond. Facial and vocal measurements were assessed in relation to schizophrenia symptom severity using the Positive and Negative Syndrome Scale. RESULTS: Vocal markers including speech prevalence, vocal jitter, fundamental frequency, and vocal intensity demonstrated specificity as markers of negative symptom severity, while measurement of facial expressivity demonstrated itself as a robust marker of overall schizophrenia symptom severity. CONCLUSIONS: Established facial and vocal measurements, collected remotely in schizophrenia patients via smartphones in response to automated task prompts, demonstrated accuracy as markers of schizophrenia symptom severity. Clinical implications are discussed.

Digitally Enabled, Patient-Centric Clinical Trials: Shifting the Drug Development Paradigm.

The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site-centric to a patient-centric model. Merck's (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck's digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient-centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real-time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure-response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient-centric, digitally enabled trials will also be discussed.

Linking forest management to moose population trends: The role of the nutritional landscape.

Forested lands in the western USA have undergone changes in management and condition that are resulting in a shift towards climax vegetation. These changes can influence the quality and quantity of forage for herbivores that rely on early-seral plants. To evaluate how management of forested landscapes might affect nutrition for Shiras moose (A. a. shirasi) at large spatial scales, we focused on shrubs and evaluated summer diet composition, forage availability, and forage quality across 21 population management units encompassing >36,000 km2 in northern Idaho, USA. We identified 17 shrub species in the diets of moose, 11 of which comprised the bulk of the diets. These forage shrubs varied markedly in both energy (mean digestible energy for leaves ranged from 9.62 to 12.89 kJ/g) and protein (mean digestible protein for leaves ranged from 1.73 to 7.90%). By adapting established field sampling methods and integrating recent advances in remote sensing analyses in a modeling framework, we predicted approximations of current and past (i.e., 1984) quantities of forage shrubs across northern Idaho. We also created a qualitative index of population trend for moose across population management units using harvest data. Predicted quantities of forage shrubs varied widely across the study area with generally higher values at more northern latitudes. The quantity of forage shrubs was estimated to have declined over the past 30 years in about half of the population management units, with the greatest declines predicted for high-energy forage species. The population trend index was correlated with the percent change in availability of moderate-energy forage shrubs, indicating that availability of forage shrubs and change in availability over time might be affecting population dynamics for moose in northern Idaho. Our study highlights the importance of assessing how changes in forest management across broad spatiotemporal extents could affect wildlife and their habitats.

Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites.

Herbivores that forage on chemically defended plants consume complex mixtures of plant secondary metabolites (PSMs). However, the mechanisms by which herbivores tolerate mixtures of PSMs are relatively poorly understood. As such, it remains difficult to predict how PSMs, singly or as complex mixtures, influence diet selection by herbivores. Although relative rates of detoxification of PSMs have been used to explain tolerance of PSMs by dietary specialist herbivores, few studies have used the rate of detoxification of individual PSMs to understand dietary preferences of individual herbivores for individual versus mixtures of PSMs. We coupled in vivo experiments using captive feeding trials with in vitro experiments using enzymatic detoxification assays to evaluate the dietary preferences and detoxification capacities of pygmy rabbits (Brachylagus idahoensis), dietary specialists on sagebrush (Artemisia spp.), and mountain cottontails (Sylvilagus nuttallii), dietary generalists. We compared preference for five single PSMs in sagebrush compared to a mixture containing those same five PSMs. We hypothesized that relative preference for individual PSMs would coincide with faster detoxification capacity for those PSMs by specialists and generalists. Pygmy rabbits generally showed little preference among individual PSMs compared to mixed PSMs, whereas mountain cottontails exhibited stronger preferences. Pygmy rabbits had faster detoxification capacities for all PSMs and consumed higher concentrations of individual PSMs versus a mixture than cottontails. However, detoxification capacity for an individual PSM did not generally coincide with preferences or avoidance of individual PSMs by either species. Cottontails avoided, but pygmy rabbits preferred, camphor, the PSM with the slowest detoxification rate by both species. Both species avoided ß-pinene despite it having one of the fastest detoxification rate. Taken together our in vivo and in vitro results add to existing evidence that detoxification capacity is higher in dietary specialist than generalist herbivores. However, results also suggest that alternative mechanisms such as absorption and the pharmacological action of individual or mixtures of PSMs may play a role in determining preference of PSMs within herbivore species.

Seasonal temperature acclimatization in a semi-fossorial mammal and the role of burrows as thermal refuges.

Small mammals in habitats with strong seasonal variation in the thermal environment often exhibit physiological and behavioral adaptations for coping with thermal extremes and reducing thermoregulatory costs. Burrows are especially important for providing thermal refuge when above-ground temperatures require high regulatory costs (e.g., water or energy) or exceed the physiological tolerances of an organism. Our objective was to explore the role of burrows as thermal refuges for a small endotherm, the pygmy rabbit (Brachylagus idahoensis), during the summer and winter by quantifying energetic costs associated with resting above and below ground. We used indirect calorimetry to determine the relationship between energy expenditure and ambient temperature over a range of temperatures that pygmy rabbits experience in their natural habitat. We also measured the temperature of above- and below-ground rest sites used by pygmy rabbits in eastern Idaho, USA, during summer and winter and estimated the seasonal thermoregulatory costs of resting in the two microsites. Although pygmy rabbits demonstrated seasonal physiological acclimatization, the burrow was an important thermal refuge, especially in winter. Thermoregulatory costs were lower inside the burrow than in above-ground rest sites for more than 50% of the winter season. In contrast, thermal heterogeneity provided by above-ground rest sites during summer reduced the role of burrows as a thermal refuge during all but the hottest periods of the afternoon. Our findings contribute to an understanding of the ecology of small mammals in seasonal environments and demonstrate the importance of burrows as thermal refuge for pygmy rabbits.

Interacting effects of ambient temperature and food quality on the foraging ecology of small mammalian herbivores.

Both temperature and diet quality play an important role in the time and energy budgets of small mammalian herbivores. However, little is known about how temperature and diet quality interact to influence diet selection, nutrient extraction, and energetics, and how these effects might differ among species. Therefore, we examined the effects of diet quality and temperature on aspects of the foraging ecology of two species of lagomorphs, pygmy rabbits (Brachylagus idahoensis), which are small dietary specialists, and mountain cottontail rabbits (Sylvilagus nuttallii), which are larger dietary and habitat generalists. In a series of feeding experiments, we investigated 1) the effects of temperature on selection of plant fiber and the plant secondary metabolite 1,8 cineole in their diets, 2) effects of temperature and plant fiber on daily intake, digestion, and passage of food, 3) effects of plant fiber and 1,8 cineole on resting metabolic rate, and 4) how these interactions differ between the rabbit species. Both species chose to eat more total food and a greater proportion of high fiber food that passed more quickly through the digestive system in colder temperatures. However, temperature did not affect how much 1,8 cineole the rabbits consumed nor how thoroughly they digested food. Food quality affected how well they digested the dry matter in the food, but not their resting metabolic rate. Understanding how the interactions between ambient temperature and food quality affect selection of diets and intake by small mammalian herbivores, and the physiological mechanisms governing these choices, is useful for predicting how these species might respond to changes in both temperature and food quality and inform conservation and restoration strategies.

Evaluation of micro-GPS receivers for tracking small-bodied mammals.

GPS telemetry markedly enhances the temporal and spatial resolution of animal location data, and recent advances in micro-GPS receivers permit their deployment on small mammals. One such technological advance, snapshot technology, allows for improved battery life by reducing the time to first fix via postponing recovery of satellite ephemeris (satellite location) data and processing of locations. However, no previous work has employed snapshot technology for small, terrestrial mammals. We evaluated performance of two types of micro-GPS (< 20 g) receivers (traditional and snapshot) on a small, semi-fossorial lagomorph, the pygmy rabbit (Brachylagus idahoensis), to understand how GPS errors might influence fine-scale assessments of space use and habitat selection. During stationary tests, microtopography (i.e., burrows) and satellite geometry had the largest influence on GPS fix success rate (FSR) and location error (LE). There was no difference between FSR while animals wore the GPS collars above ground (determined via light sensors) and FSR generated during stationary, above-ground trials, suggesting that animal behavior other than burrowing did not markedly influence micro-GPS errors. In our study, traditional micro-GPS receivers demonstrated similar FSR and LE to snapshot receivers, however, snapshot receivers operated inconsistently due to battery and software failures. In contrast, the initial traditional receivers deployed on animals experienced some breakages, but a modified collar design consistently functioned as expected. If such problems were resolved, snapshot technology could reduce the tradeoff between fix interval and battery life that occurs with traditional micro-GPS receivers. Our results suggest that micro-GPS receivers are capable of addressing questions about space use and resource selection by small mammals, but that additional techniques might be needed to identify use of habitat structures (e.g., burrows, tree cavities, rock crevices) that could affect micro-GPS performance and bias study results.

Selection of food patches by sympatric herbivores in response to concealment and distance from a refuge.

Small herbivores face risks of predation while foraging and are often forced to trade off food quality for safety. Life history, behaviour, and habitat of predator and prey can influence these trade-offs. We compared how two sympatric rabbits (pygmy rabbit, Brachylagus idahoensis; mountain cottontail, Sylvilagus nuttallii) that differ in size, use of burrows, and habitat specialization in the sagebrush-steppe of western North America respond to amount and orientation of concealment cover and proximity to burrow refuges when selecting food patches. We predicted that both rabbit species would prefer food patches that offered greater concealment and food patches that were closer to burrow refuges. However, because pygmy rabbits are small, obligate burrowers that are restricted to sagebrush habitats, we predicted that they would show stronger preferences for greater cover, orientation of concealment, and patches closer to burrow refuges. We offered two food patches to individuals of each species during three experiments that either varied in the amount of concealment cover, orientation of concealment cover, or distance from a burrow refuge. Both species preferred food patches that offered greater concealment, but pygmy rabbits generally preferred terrestrial and mountain cottontails preferred aerial concealment. Only pygmy rabbits preferred food patches closer to their burrow refuge. Different responses to concealment and proximity to burrow refuges by the two species likely reflect differences in perceived predation risks. Because terrestrial predators are able to dig for prey in burrows, animals like pygmy rabbits that rely on burrow refuges might select food patches based more on terrestrial concealment. In contrast, larger habitat generalists that do not rely on burrow refuges, like mountain cottontails, might trade off terrestrial concealment for visibility to detect approaching terrestrial predators. This study suggests that body size and evolutionary adaptations for using habitat, even in closely related species, might influence anti-predator behaviors in prey species.

An Integrated Strategy for Implementation of Dried Blood Spots in Clinical Development Programs.

Dried blood spot (DBS) sample collection has gained increased interest across the pharmaceutical industry as a potential alternative to plasma for pharmacokinetic (PK) evaluations. However, regulatory guidelines and examples of late-stage clinical trial applications in the literature are lacking. This paper communicates Merck's strategy for the implementation of DBS exemplified by experience on a late-stage program (MK-8931). In this program, DBS was proposed as the sole matrix for phase 3 studies to decrease logistical burden in an aging target patient population (Alzheimer's disease). In vitro and bioanalytical tests demonstrated initial method feasibility and suitability for further evaluations in the clinic. An in vivo dataset was developed initially in healthy subjects (phase 1 study) and then in patients (phase 2/3 study) to establish a quantitative relationship between the blood and plasma concentrations (bridging dataset) using descriptive and population PK analyses. This allowed for PK conclusions to be seamlessly drawn across the clinical program without impact from the choice of matrix. This integrated information package (in vitro, bioanalytical and clinical) was presented to major regulatory agencies (FDA and EMA) for regulatory input. Based on this package, regulatory concurrence was gained on accepting DBS as the sole matrix in late-stage clinical trials.

Modeling trade-offs between plant fiber and toxins: a framework for quantifying risks perceived by foraging herbivores.

When selecting habitats, herbivores must weigh multiple risks, such as predation, starvation, toxicity, and thermal stress, forcing them to make fitness trade-offs. Here, we applied the method of paired comparisons (PC) to investigate how herbivores make trade-offs between habitat features that influence selection of food patches. The method of PC measures utility and the inverse of utility, relative risk, and makes trade-offs and indifferences explicit by forcing animals to make choices between two patches with different types of risks. Using a series of paired-choice experiments to titrate the equivalence curve and find the marginal rate of substitution for one risk over the other, we evaluated how toxin-tolerant (pygmy rabbit Brachylagus idahoensis) and fiber-tolerant (mountain cottontail rabbit Sylviagus nuttallii) herbivores differed in their hypothesized perceived risk of fiber and toxins in food. Pygmy rabbits were willing to consume nearly five times more of the toxin 1,8-cineole in their diets to avoid consuming higher levels of fiber than were mountain cottontails. Fiber posed a greater relative risk for pygmy rabbits than cottontails and cineole a greater risk for cottontails than pygmy rabbits. Our flexible modeling approach can be used to (1) quantify how animals evaluate and trade off multiple habitat attributes when the benefits and risks are difficult to quantify, and (2) integrate diverse risks that influence fitness and habitat selection into a single index of habitat value. This index potentially could be applied to landscapes to predict habitat selection across several scales.

Plant protein and secondary metabolites influence diet selection in a mammalian specialist herbivore.

For herbivores, nutrient intake is limited by the relatively low nutritional quality of plants and high concentrations of potentially toxic defensive compounds (plant secondary metabolites, PSMs) produced by many plants. In response to phytochemical challenges, some herbivores selectively forage on plants with higher nutrient and lower PSM concentrations relative to other plants. Pygmy rabbits (Brachylagus idahoensis) are dietary specialists that feed on sagebrush (Artemisia spp.) and forage on specific plants more than others within a foraging patch. We predicted that the plants with evidence of heavy foraging (browsed plants) would be of higher dietary quality than plants that were not browsed (unbrowsed). We used model selection to determine which phytochemical variables best explained the difference between browsed and unbrowsed plants. Higher crude protein increased the odds that plants would be browsed by pygmy rabbits and the opposite was the case for certain PSMs. Additionally, because pygmy rabbits can occupy foraging patches (burrows) for consecutive years, their browsing may influence the nutritional and PSM constituents of plants at the burrows. In a post hoc analysis, we did not find a significant relationship between phytochemical concentrations, browse status and burrow occupancy length. We concluded that pygmy rabbits use nutritional and chemical cues while making foraging decisions.

Effects of genetic management on reproduction, growth, and survival in captive endangered pygmy rabbits (Brachylagus idahoensis).

A quarter of all lagomorph species worldwide are threatened with extinction. Captive breeding programs, such as that developed for the Columbia Basin (CB) pygmy rabbit (Brachylagus idahoensis), sometimes are implemented as emergency conservation measures to restore small, genetically distinct populations. However, small source populations also may have low genetic diversity, which may influence attributes related to fitness, including growth, survival, and reproduction. We used mixed-effects regression models to explore the influence of genetic pedigree (% CB) on pairing success, growth, and survival during the 10-year captive breeding program at Washington State University, which included controlled pairings and outbreeding with pygmy rabbits from Idaho. Pairing success, juvenile growth, and juvenile survival declined with increasing CB pedigree of 1 or both parents, suggesting inbreeding depression among the small number of related founders. Demographic variables such as age, sex, and previous pregnancies, and environmental variables such as month and temperature at birth also were associated with production of pygmy rabbits. Our study illustrates the difficulty of retaining a unique genome of a small source population while simultaneously producing enough rabbits for restoration into natural habitat as part of endangered species recovery programs.

Mechanisms for eliminating monoterpenes of sagebrush by specialist and generalist rabbits.

Pygmy rabbits (Brachylagus idahoensis) are one of only three vertebrates that subsist virtually exclusively on sagebrush (Artemisia spp.), which contains high levels of monoterpenes that can be toxic. We examined the mechanisms used by specialist pygmy rabbits to eliminate 1,8-cineole, a monoterpene of sagebrush, and compared them with those of cottontail rabbits (Sylvilagus nuttalli), a generalist herbivore. Rabbits were offered food pellets with increasing concentrations of cineole, and we measured voluntary intake and excretion of cineole metabolites in feces and urine. We expected pygmy rabbits to consume more, but excrete cineole more rapidly by using less-energetically expensive methods of detoxification than cottontails. Pygmy rabbits consumed 3-5 times more cineole than cottontails relative to their metabolic body mass, and excreted up to 2 times more cineole metabolites in their urine than did cottontails. Urinary metabolites excreted by pygmy rabbits were 20 % more highly-oxidized and 6 times less-conjugated than those of cottontails. Twenty percent of all cineole metabolites recovered from pygmy rabbits were in feces, whereas cottontails did not excrete fecal metabolites. When compared to other mammals that consume cineole, pygmy rabbits voluntarily consumed more, and excreted more cineole metabolites in feces, but they excreted less oxidized and more conjugated cineole metabolites in urine. Pygmy rabbits seem to have a greater capacity to minimize systemic exposure to cineole than do cottontails, and other cineole-consumers, by minimizing absorption and maximizing detoxification of ingested cineole. However, mechanisms that lower systemic exposure to cineole may come with a higher energetic cost in pygmy rabbits than in other mammalian herbivores.

Characterizing gonadal and adrenal activity by fecal steroid analyses in pygmy rabbits (Brachylagus idahoensis).

In 2001, the sudden collapse of the Columbia Basin population of pygmy rabbits prompted the initiation of a captive breeding program to facilitate reintroduction, but reproductive success in captivity has not met expectations. Therefore, the objective of this study was to characterize the reproductive and adrenal endocrinology of this endangered rabbit species so that appropriate management strategies could be developed to monitor animal welfare and increase reproduction. Fecal samples were collected from 27 female pygmy rabbits over three breeding and non-breeding seasons. HPLC analyses verified the presence of progesterone in the excreta of pygmy rabbits, but the majority of progestagen metabolites were unidentified polar compounds. By contrast, >70% of glucocorticoid immunoactivity was associated with cortisol. Longitudinal fecal hormone profiles during pregnancy were characterized by a large spike in progestagens shortly after mating, a gradual increase in progestagen and glucocorticoid concentrations throughout gestation and a return of hormones to baseline soon after birth (Day 24). The spike in progestagens 1 day after mating was a significant discovery for this species and appears to provide a reliable means of determining if a successful mating has occurred. Seasonal analyses of hormone excretion found that progestagen baselines did not vary between the breeding and non-breeding seasons, but, as expected, were highest during the breeding season in association with pregnancy. Across seasons, the lowest concentrations of glucocorticoids were associated with the highest rates of offspring production and survival, suggesting a possible link between heightened adrenal activity and lowered reproductive fitness in pygmy rabbits.

Inter-population differences in the tolerance of a marsupial folivore to plant secondary metabolites.

Plant secondary metabolites (PSMs) strongly influence diet selection by mammalian herbivores. Concentrations of PSMs vary within and among plant species, and across landscapes. Therefore, local adaptations may cause different populations of herbivores to differ in their ability to tolerate PSMs. Here, we tested the food intake responses of three populations of a marsupial folivore, the common brushtail possum (Trichosurus vulpecula Kerr), from different latitudes and habitat types, to four types of PSMs. We found clear variation in the responses of northern and southern Australian possums to PSMs. Brushtail possums from southern Australia showed marked decreases in food intake in response to all four PSMs, while the two populations from northern Australia were not as sensitive and their responses did not differ from one another. These results were unexpected, based on our understanding of the experiences of these populations with PSMs in the wild. Our results suggest that geographically separated populations of possums may have evolved differing abilities to cope with PSMs, as a result of local adaptation to their natural environments. Our results provide the basis for future studies to investigate the mechanisms by which populations of mammalian species differ in their ability to tolerate PSMs.

Revisiting the dietary niche: When is a mammalian herbivore a specialist?

Understanding dietary specialization in herbivores has theoretical and practical implications in ecology, yet defining niche breadth consistently has been problematic. To increase clarity and communication among ecologists and among disciplines (i.e., chemists, pharmacologists), we propose a specialization key for mammalian herbivores that assigns "obligatory" and "facultative" modifiers to the terms "specialist" and "generalist". These modifiers are assigned based on (1) relative breadth of the animal's realized niche and diet (what it eats), (2) relative breadth of the fundamental niche and available diet (what it could eat), (3) the extent of chemical or physical characteristics, termed "difficulty", that make food items either low in value or unpalatable to most herbivores, and (4) relevant temporal and spatial scales at which diets and niche breadth were measured. Obligatory specialists always have a narrow realized niche consisting of difficult food items, and morphological adaptations and/or the loss of redundant behavioral flexibility that effectively limit their fundamental niches, precluding them from expanding their diet under changed environmental conditions. Facultative specialists have a consistently narrow realized niche for difficult foods during at least one spatial or temporal scale, but have a broad enough fundamental niche to allow them to expand their diet to include less difficult foods when environmental conditions allow. Facultative generalists have the broadest fundamental niche, allowing them to consume a wide variety of foods. However, they may occasionally demonstrate a narrow realized niche, focused on less difficult plants than is the case with specialists. Finally, the obligatory generalists always have a wide realized niche because of a relatively narrow fundamental niche, precluding them from eating much of any difficult plant. We summarize hypothesized characteristics of mammalian herbivores in each of the four categories of specialization. We demonstrate the need for further work on defining the realized and fundamental niches, comparing among herbivores across categories conducted under similar conditions, and understanding the nature of trade-offs required for specialization and generalization for both community and phylogenetically based analyses.

PhRMA white paper on ADME pharmacogenomics.

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross-industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003-2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug-metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

UV-B effects on the nutritional chemistry of plants and the responses of a mammalian herbivore.

Stratospheric ozone depletion has caused ground-level ultraviolet-B (UV-B) radiation to rise in temperate latitudes of both hemispheres. Because the effects of enhanced UV-B radiation on the nutrition of food consumed by mammalian herbivores are unknown, we measured nutritional and chemical constituents of 18 forages and related changes to in vitro dry matter digestibility. We also measured intake and in vivo digestibility of Pacific willow (Salix lasiandra) and alfalfa (Medicago sativa L.) by blue duikers (Cephalophus monticola). Forages were irradiated for 3 months with ambient (1x) or supplemental (1.6 x) UV-B radiation representing a 15% ozone depletion for Pullman, Washington, USA. Enhanced UV-B radiation had minimal and inconsistent effects on the nutritional content, in vitro dry matter digestibility, and protein-binding capacity of forages. However, flavonoid compounds increased in seven of the 13 forbs and woody dicots that were evaluated. Flavonoids were found to decrease only in yarrow (Achillea millefolium). When offered simultaneously, blue duikers preferred 1x and 1.6 x UV-B irradiated plants of alfalfa equally, but ate 26% less willow grown under 1.6 x UV-B radiation. However, when fed to duikers in separate feeding experiments, total dry matter intake and in vivo digestibility of dry matter, fiber, protein, and apparent energy did not differ between alfalfa and willow grown under 1x and 1.6 x UV-B radiation. We conclude that expected increases in UV-B radiation from ozone depletion would have minimal effects on intake and digestion of ruminant herbivores.