Importance of nutritional and anti-parasite strategies in the foraging decisions of horses: an experimental test

The primary goal of foraging herbivores is to maximise the net rate of intake of digestible energy (or of a limiting nutrient). However, foraging strategies of herbivores are also sensitive to other selective forces (e.g. predation, parasites), which may modify their choice of feeding patches. Horses feed in spatially complex swards, and allocate their time among patches which vary both in terms of their nutritional benefits, and the risk of parasitism. It has long been suggested that horses allocate time among patches principally in relation to the risk of parasitism, though the nutritional costs and benefits of different foraging choices must play some role too. In this study, we investigated the roles of nutritional and anti-parasite factors in foraging decisions by horses. Six naturally parasitized and six unparasitized two-year-old geldings were allowed to graze from pairs of trays (112×72 cm) with swards at two heights (tall: 52 cm, medium: 15 cm) and two levels of contamination (280 g m⁻² of faeces, no faeces) in a latin square, pair-wise design with six different choices. In nutritional terms the differences between the swards were slight: the tall sward provided larger bite sizes and higher intake rates (+36%). Feeding motivation was not high, and the faecal stimulus was strong. The horses selected uncontaminated swards when the nutritional benefits were identical, and tall swards in virtually all circumstances. Contamination of the preferred tall sward (i.e. a test of the tradeoff between anti-parasite and nutritional strategies) had little effect on its selection by the horses. Their parasite status also had little effect: both groups selected the tall sward in the tradeoff (though this was only a trend for the non-parasitised group in one analysis). We conclude that patch selection by horses in these particular conditions was driven principally by their nutritional strategy.     

N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery,lead optimization and demonstration of off-target effect in a diabetes model

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp³ content (Fsp³) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE?=?0.3, ΔFsp³?=?0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.     

Importance of the connectivity of Spanish stopovers for Black Storks

Capsule?Sixteen Black Storks (Ciconia nigra) were tracked by satellite during their autumnal and spring migrations in order to identify their major stopover sites and connections between stopovers in Europe and Africa. Among journeys with stopovers, the longest distance that a stork travelled without stopover was 2433?km (defined here as ‘accessible distance’) meaning that those storks which have stopovers use only a single stopover on average, and this is usually in Spain. We identified nine crucial stopovers (seven in Spain and two in Africa) with high connectivity highlighting the importance of Spanish stopover locations on the flyway of Black Storks.     

Rapid Simultaneous Estimation of Aboveground Biomass and Tree Diversity Across Neotropical Forests: A Comparison of Field Inventory Methods

A standardized rapid inventory method providing information on both tree species diversity and aboveground carbon stocks in tropical forests will be an important tool for evaluating efforts to conserve biodiversity and to estimate the carbon emissions that result from deforestation and degradation (REDD). Herein, we contrast five common plot methods differing in shape, size, and effort requirements to estimate tree diversity and aboveground tree biomass (AGB). We simulated the methods across six Neotropical forest sites that represent a broad gradient in forest structure, tree species richness, and floristic composition, and we assessed the relative performance of methods by evaluating the bias and precision of their estimates of AGB and tree diversity. For a given sample of forest area, a ‘several small’ (< 1 ha) sampling strategy led to a smaller coefficient of variation (CV) in the estimate of AGB than a ‘few large’ one. The effort (person‐days) required to achieve an accurate AGB estimate (< 10% CV), however, was greater for the smallest plots (0.1 ha) than for a compromise approach using 0.5 ha modified Gentry plots, which proved to be the most efficient method to estimate AGB across all forest types. Gentry plots were also the most efficient at providing accurate estimates of tree diversity (< 10% CV of Hill number). We recommend the use of the 0.5 ha modified Gentry plot method in future rapid inventories, and we discuss a set of criteria that should inform any choice of inventory method.     

Comparative breeding performance of Marsh Harriers Circus aeruginosus along a gradient of land‐use intensification and implications for population management

Assessing variation in breeding performance in relation to habitat characteristics may provide insights into predicting the consequences of land‐use change on species ecology and population dynamics. We compared four Marsh Harrier Circus aeruginosus populations subject to similar environmental conditions, but which differed in habitat composition, ranging from natural habitats to intensively cultivated areas. Using a 6‐year dataset, we characterized breeding habitat and diet in these four study sites, and analysed breeding performance in relation to this gradient of land‐use intensification. There was minimal variation in breeding performance between study years but consistent variation between study sites. Unexpectedly, Marsh Harriers breeding in intensively cultivated habitats had higher reproductive success than those breeding in more natural habitats, which, however, hosted higher breeding densities, so overall net population productivity (fledglings per unit area) was similar across sites. This resulted from combined effects of density‐dependence and different predation rates between study sites. The colonization of intensive farmland habitats may not necessarily impact negatively on population sustainability when breeding success and population density are traded against each other. However, our findings should not mask longer‐term conservation issues for populations breeding in these intensively managed areas, and further studies should assess potential long‐term negative effects of occupancy of human‐altered habitat.     

Procoagulant Platelets Form an α-Granule Protein-covered “Cap” on Their Surface That Promotes Their Attachment to Aggregates

Strongly activated “coated” platelets are characterized by increased phosphatidylserine (PS) surface expression, α-granule protein retention, and lack of active integrin α_IIbβ₃. To study how they are incorporated into thrombi despite a lack of free activated integrin, we investigated the structure, function, and formation of the α-granule protein “coat.” Confocal microscopy revealed that fibrin(ogen) and thrombospondin colocalized as “cap,” a single patch on the PS-positive platelet surface. In aggregates, the cap was located at the point of attachment of the PS-positive platelets. Without fibrin(ogen) retention, their ability to be incorporated in aggregates was drastically reduced. The surface fibrin(ogen) was strongly decreased in the presence of a fibrin polymerization inhibitor GPRP and also in platelets from a patient with dysfibrinogenemia and a fibrinogen polymerization defect. In contrast, a fibrinogen-clotting protease ancistron increased the amount of fibrin(ogen) and thrombospondin on the surface of the PS-positive platelets stimulated with collagen-related peptide. Transglutaminases are also involved in fibrin(ogen) retention. However, platelets from patients with factor XIII deficiency had normal retention, and a pan-transglutaminase inhibitor T101 had only a modest inhibitory effect. Fibrin(ogen) retention was normal in Bernard-Soulier syndrome and kindlin-3 deficiency, but not in Glanzmann thrombasthenia lacking the platelet pool of fibrinogen and α_IIbβ₃. These data show that the fibrin(ogen)-covered cap, predominantly formed as a result of fibrin polymerization, is a critical mechanism that allows coated (or rather “capped”) platelets to become incorporated into thrombi despite their lack of active integrins.     

Seasonal Variations in Clock‐Gene Expression in Atlantic Salmon (Salmo salar)

In homeothermic vertebrates inhabiting temperate latitudes, it is clear that the seasonal changes in daylength are decoded by the master circadian clock, which through secondary messengers (like pineal melatonin secretion) entrains rhythmic physiology to local conditions. In contrast, the entrainment and neuroendocrine regulation of rhythmic physiology in temperate teleosts is not as clear, primarily due to the lack of understanding of the clock gene system in these species. In this study, we analyzed the diel expression of the clock‐genes in brains of Atlantic salmon, a species that is both highly photoperiodic and displays robust clock‐controlled behavior. Atlantic salmon parr were acclimated to either long‐day (LD) or short‐day (SD) photoperiods for one month and thereafter sampled at 4 h intervals over a 24 h cycle. Clock, Bmal1, Per2, and Cry2 were all actively expressed in salmon brain homogenates and, with the exception of Per2, all displayed rhythmic expression under SD photoperiods that parallels that reported in zebrafish. Interestingly, daylength significantly altered the mRNA expression of all clock genes studied, with Clock, Bmal1, and Per2 all becoming arrhythmic under the LD compared to SD photoperiod, while Cry2 expression was phase delayed under LD. It is thus proposed that the clock‐gene system is actively expressed in Atlantic salmon, and, furthermore, as has been reported in homeothermic vertebrates, it appears that clock expression is daylength‐dependent.     

18F-FDG Is a Surrogate Marker of Therapy Response and Tumor Recovery after Drug Withdrawal during Treatment with a Dual PI3K/mTOR Inhibitor in a Preclinical Model of Cisplatin-Resistant Ovarian Cancer

AIM: Targeting the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming chemoresistance in ovarian cancer. We investigated the capability of ¹⁸F-fluororodeoxyglucose (¹⁸F-FDG) small-animal positron emission tomography (SA-PET) to predict the effects of a dual PI3K/mTOR inhibitor (BEZ-235) in a cisplatin-resistant ovarian cancer model. METHODS: In a first experiment, nude rats bearing subcutaneous SKOV3 tumors received BEZ-235 for 3 days given alone or after paclitaxel and were compared to controls (either untreated or that were given the excipients of paclitaxel and BEZ-235). SA-PET was performed at baseline, on day 3, and day 7. In a second experiment aiming at further exploring the kinetics of ¹⁸F-FDG tumor uptake during the first 48 hours following drug cessation, untreated controls were compared to rats receiving BEZ-235, which were imaged at baseline, on day 3, on day 4, and on day 5. SA-PET results were compared to cell proliferation assessment (Ki-67), PI3K/mTOR downstream target expression studies (pAKT and phospho-eukaryotic translation initiation factor 4E-binding protein 1), and apoptosis evaluation (cleaved caspase-3). RESULTS: In the first experiment, BEZ-235, compared to untreated controls, induced a marked decrease in ¹⁸F-FDG uptake on day 3, which was correlated to a significant decrease in cell proliferation and to a significant PI3K/mTOR pathway inhibition. No tumor necrosis or apoptosis occurred. Four days following treatment cessation, tumor recovery (in terms of PI3K/mTOR inhibition and cell proliferation) occurred and was identified by ¹⁸F-FDG SA-PET. Paclitaxel plus BEZ-235 showed results similar to BEZ-235 alone. In the second experiment, PI3K/mTOR pathways exhibited partial recovery as early as 24 hours following treatment cessation, but both ¹⁸F-FDG SA-PET and cell proliferation remained unchanged. CONCLUSIONS:¹⁸F-FDG SA-PET is a surrogate marker of target inhibition during treatment with BEZ-235 and predicts tumor recovery 4 days after drug withdrawal, but not during the first 48 hours following drug cessation, when a lag between PI3K/mTOR pathway recovery and metabolic recovery is observed. ¹⁸F-FDG SA-PET could be used for therapy monitoring of PI3K/mTOR inhibitors, but our results also raise questions regarding the potential impact of the delay between PET imaging and the last drug intake on the accuracy of FDG imaging.     

New Findings for Maternal Mortality Age Patterns: Aggregated Results for 38 Countries

Background

With recent results showing a global decline in overall maternal mortality during the last two decades and with the target date for achieving the Millennium Development Goals only four years away, the question of how to continue or even accelerate the decline has become more pressing. By knowing where the risk is highest as well as where the numbers of deaths are greatest, it may be possible to re-direct resources and fine-tune strategies for greater effectiveness in efforts to reduce maternal mortality.

Methods

We aggregate data from 38 Demographic and Health Surveys that included a maternal mortality module and were conducted in 2000 or later to produce maternal mortality ratios, rates, and numbers of deaths by five year age groups, separately by residence, region, and overall mortality level.

Findings

The age pattern of maternal mortality is broadly similar across regions, type of place of residence, and overall level of maternal mortality. A “J” shaped curve, with markedly higher risk after age 30, is evident in all groups. We find that the excess risk among adolescents is of a much lower magnitude than is generally assumed. The oldest age groups appear to be especially resistant to change. We also find evidence of extremely elevated risk among older mothers in countries with high levels of HIV prevalence.

Conclusions

The largest number of deaths occurs in the age groups from 20-34, largely because those are the ages at which women are most likely to give birth so efforts directed at this group would most effectively reduce the number of deaths. Yet equity considerations suggest that efforts also be directed toward those most at risk, i.e., older women and adolescents. Because women are at risk each time they become pregnant, fulfilling the substantial unmet need for contraception is a cross-cutting strategy that can address both effectiveness and equity concerns.