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Understanding the consequences of global change for animal movement is a major issue for conservation and management. In particular, habitat fragmentation generates increased densities of linear landscape features that can impede movements.While the influence of these features on animal movements has been intensively investigated, they may also play a key role at broader spatial scales (e.g. the home range scale) as resources, cover from predators/humans, corridors/barriers or landmarks. How space use respond to varying densities of linear features has been mostly overlooked in large herbivores, in contrast to studies done on predators. Focusing on large herbivores should provide additional insights to understand how animals solve the trade‐off between energy acquisition and mortality risk.Here, we investigated the role of anthropogenic (roads and tracks) and natural (ridges, valley bottoms and forest edges) linear features on home range features in five large herbivores. We analysed an extensive GPS monitoring database of 710 individuals across nine populations, ranging from mountain areas mostly divided by natural features to lowlands that were highly fragmented by anthropogenic features.Nearly all of the linear features studied were found at the home range periphery, suggesting that large herbivores primarily use them as landmarks to delimit their home range. In contrast, for mountain species, ridges often occurred in the core range, probably related to their functional role in terms of resources and refuge. When the density of linear features was high, they no longer occurred predominantly at the home range periphery, but instead were found across much of the home range. We suggest that, in highly fragmented landscapes, large herbivores are constrained by the costs of memorising the spatial location of key features, and by the requirement for a minimum area to satisfy their vital needs.These patterns were mostly consistent in both males and females and across species, suggesting that linear features have a preponderant influence on how large herbivores perceive and use the landscape. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (HSP90) is a critical target for anticancer and anti-fungal-infection therapies due to its central role as a molecular chaperone involved in protein folding and activation. In this study, we developed in vitro Förster Resonance Energy Transfer (FRET) assays to characterize the binding of C. albicans HSP90 to its co-chaperone Sba1, as well as that of the homologous human HSP90α to p23. The assay for human HSP90α binding to p23 enables selectivity assessment for compounds aimed to inhibit the binding of C. albicans HSP90 to Sba1 without affecting the physiological activity of human HSP90α. The combination of the two assays is important for antifungal drug development, while the assay for human HSP90α can potentially be used on its own for anticancer drug discovery. Since ATP binding of HSP90 is a prerequisite for HSP90-Sba1/p23 binding, ATP-competitive inhibitors can be identified with the assays. The specificity of binding of fusion protein constructs—HSP90-mNeonGreen (donor) and Sba1-mScarlet-I (acceptor)—to each other in our assay was confirmed via competitive inhibition by both non-labeled Sba1 and known ATP-competitive inhibitors. We utilized the developed assays to characterize the stability of both HSP90–Sba1 and HSP90α–p23 affinity complexes quantitatively. Kd values were determined and assessed for their precision and accuracy using the 95.5% confidence level. For HSP90-Sba1, the precision confidence interval (PCI) was found to be 70–120 (100 ± 20) nM while the accuracy confidence interval (ACI) was 100–130 nM. For HSP90α-p23, PCI was 180–260 (220 ± 40) nM and ACI was 200–270 nM. The developed assays were used to screen a nucleoside-mimetics library of 320 compounds for inhibitory activity against both C. albicans HSP90-Sba1 and human HSP90α-p23 binding. No novel active compounds were identified. Overall, the developed assays exhibited low data variability and robust signal separation, achieving Z factors > 0.5. [ABSTRACT FROM AUTHOR]

Recreational activities often result in a spatial and/or temporal activity shift in wildlife. With the concurrent development of outdoor activities and increase in temperatures due to climate change, mountain species face increasing pressures in terms of managing their activity pattern to limit both risk exposure and thermal discomfort. Using more than 15 years of long-term GPS and activity sensor data, we investigated how female northern chamois, Rupicapra rupicapra rupicapra , adjust their summer circadian activity to spatiotemporal variation in both temperatures and hikers' presence. Chamois' behaviour was more affected by high temperatures than by hikers' presence. During the hottest days, they shifted their activity peak earlier in the morning, were more active at night and during activity peaks, less active during daytime and had longer morning and evening peaks compared to the coldest days. Yet, total daily activity was only slightly different during the hottest days compared to the coldest days. Conversely, hikers' disturbance had weak effects on activity levels and on the timing of activity peaks. This is especially true for temporal disturbance (weekdays versus weekends and public holidays), possibly because most weekdays in summer fell during school holidays. Only during the hottest conditions, the morning activity peak was shorter and the evening peak longer in females living in the most exposed areas compared to females living in the least exposed areas. One possible explanation for the overall low effect of hikers' disturbance may be that behavioural changes buffering animals from high temperatures and hikers' presence (e.g. moving away from trails) allow them to just marginally modify their activity pattern. In the context of ongoing socioenvironmental changes, it is critical to conserve habitats providing thermal refuges against summer heat and protection from disturbance to mitigate potential detrimental consequences. • Chamois shifted their activity peak earlier in the morning during the hottest days. • Activity increased at night and decreased during the day with high temperatures. • Chamois' crepuscular activity was higher during the hottest than the coldest days. • Spatiotemporal variation in hikers' presence had few effects on chamois' activity. • Females in the most disturbed areas shortened morning activity on the hottest days. [ABSTRACT FROM AUTHOR]

Segregation between the sexes or related to age and/or reproductive status is common in many animal taxa, particularly in dimorphic species. The causes of this segregation remain difficult to disentangle, despite numerous attempts. This is probably due to the difficulty of obtaining sufficient data on animal behaviour (e.g. habitat use, activity budgets) and group composition (age/sex and reproductive status) during the various phases of the species' reproductive cycle. Based on an intensive long-term monitoring of a Mediterranean mouflon, Ovis gmelini musimon × Ovis sp., population, we concurrently assessed five hypotheses for segregation linked to forage selection (FSH), reproductive strategy (RSH), social preference (SPH), activity budget (ABH), and weather sensitivity (WSH). We found marked segregation between most age/sex classes. Age-dependent segregation among males was increasingly marked as their age difference increased and segregation between the sexes also increased as males became older and larger. Over the year, segregation between sex, age and reproductive status classes was lowest during the rut. We also observed the highest synchrony of activity in groups composed of individuals of similar age/sex class or reproductive status. Females occurred closer to both secure and high-quality food habitats, especially during the lambing and rearing periods, whereas males used less secure and lower quality habitats as they aged. Differences in habitat use between age/sex classes provided partial or full support for the RSH and FSH. Large males were preferentially observed at higher altitude than females during hot summer days to buffer against heat stress, in agreement with the WSH. A preference for interacting and grouping with peers that express similar activity patterns (ABH and SPH) appears to be the main driver of segregation in this population. Our study confirms the strong multifactorial nature of segregation in ungulates. [ABSTRACT FROM AUTHOR]

Recent advances in animal ecology have enabled identification of certain mechanisms that lead to the emergence of territories and home ranges from movements considered as unbounded. Among them, memory and familiarity have been identified as key parameters in cognitive maps driving animal navigation, but have been only recently used in empirical analyses of animal movements., At the same time, the influence of landscape features on movements of numerous species and on space division in territorial animals has been highlighted. Despite their potential as exocentric information in cognitive maps and as boundaries for home ranges, few studies have investigated their role in the design of home ranges of non-territorial species., Using step selection analyses, we assessed the relative contribution of habitat characteristics, familiarity preferences and linear landscape features in movement step selection of 60 GPS-collared Mediterranean mouflon Ovis gmelini musimon × Ovis sp. monitored in southern France. Then, we evaluated the influence of these movement-impeding landscape features on the design of home ranges by testing for a non-random distribution of these behavioural barriers within sections of space differentially used by mouflon., We reveal that familiarity and landscape features are key determinants of movements, relegating to a lower level certain habitat constraints (e.g. food/cover trade-off) that we had previously identified as important for this species. Mouflon generally avoid crossing both anthropogenic (i.e. roads, tracks and hiking trails) and natural landscape features (i.e. ridges, talwegs and forest edges) while moving in the opposite direction, preferentially toward familiar areas. These specific behaviours largely depend on the relative position of each movement step regarding distance to the landscape features or level of familiarity in the surroundings. We also revealed cascading consequences on the design of home ranges in which most landscape features were excluded from cores and relegated to the peripheral areas., These results provide crucial information on landscape connectivity in a context of marked habitat fragmentation. They also call for more research on the role of landscape features in the emergence of home ranges in non-territorial species using recent methodological developments bridging the gap between movements and space use patterns. [ABSTRACT FROM AUTHOR]

A series of original 2-phenyl-3-(pyridin-4-yl)imidazo[1,2- a ]pyrazines and the 3-iodo precursors, bearing a polar moiety at the C-8 position, was synthesized and evaluated for their antileishmanial activities. Two derivatives exhibited very good activity against the promastigote and the amastigote forms of Leishmania major in the micromolar to submicromolar ranges, coupled with a low cytotoxicity against macrophages and 3T3 mouse fibroblast cells. Through Lm CK1 inhibition assay, investigations of the putative molecular target of these promising antileishmanial compounds will be discussed. [ABSTRACT FROM AUTHOR]

The balance between food and perceived predation risk has been revealed as one of the primary drivers of animal habitat selection. However, few studies have investigated how spatiotemporal scales and movement/activity patterns shape responses to this food/cover trade-off while accounting for individual characteristics (e.g. sex) and for variation in predation risk (e.g. hunting) and in resource abundance/quality. We hence studied temporal changes in habitat selection of 30 GPS-collared females and 15 males of Mediterranean mouflon, Ovis gmelini musimon × Ovis sp., at two scales, i.e. 48 h home range selection within a subpopulation area (broad scale) and choice of movement steps (defined as the linear segment between two consecutive locations) according to activity state (fine scale), in southern France. During the hunting-free/food-abundant period, males selected at both scales the foraging habitats providing the best conditions for optimizing their future reproductive success and only selected areas perceived as safe during inactive steps. During the corresponding lambing period, and at both scales, females selected areas perceived as safe that should optimize lamb survival. They switched to the best foraging habitats only when lambs were weaned and only for active steps. By contrast, during hunting, when food was also scarce, both sexes selected home ranges with high proportions of the habitats perceived as safe, in which they performed all their activities. This result suggested that risk avoidance exceeded all the other individual and environmental factors in the hierarchy of the determinants of habitat selection during the hunting period. Coupling scale-specific habitat selection and activity patterns was hence decisive in disclosing how individuals fulfil their specific needs under seasonally changing levels of habitat attributes important for fitness. [ABSTRACT FROM AUTHOR]

In the context of global warming, investigating how animals buffer against the hottest conditions is a crucial issue. We focused on habitat selection in a French Mediterranean mouflon population during 2010-2012 summers. Using locations and temperatures recorded on GPScollared individuals, we assessed thermal cover provided by different habitats and analyzed sex- and scale-specific habitat selection and its thermal consequences for mouflon. At the home range scale, females (n = 26) avoided unsafe plateaux and selected steep refuges, trading off thermal cover with better conditions for lamb survival. Larger males (n = 18), not constrained by young rearing and expected to respond more strongly than smaller females to hot conditions, rather selected forests on plateaux providing thermal cover. In terms of movements, both sexes selected forests during hottest days. Males also took advantage of food and thermal cover provided by moorlands on plateaux until twilight, whereas females traded off food and thermal cover with refuges. Thermal cover significantly influenced habitat selection when temperature at the closest weather station exceeded 17.1 °C (95% confidence interval = 14.9-19.7) in males and 15.5 °C (95% confidence interval = 13.9--16.5) in females. Above these thresholds, ambient temperatures experienced by mouflon increased more slowly than temperatures at the weather station (males: 0.77 °C [95% confidence interval = 0.74-0.79] per 1 °C rise at the weather station, females: 0.75 °C [95% confidence interval = 0.73-0.76]) and more slowly than below these thresholds (males: 0.89 °C [95% confidence interval = 0.85-0.93], females: 0.94 °C [95% confidence interval = 0.89-0.98]). These findings suggested that habitat selection contributes to buffer mouflon against summer conditions but raised questions on energetic and fitness costs in areas where summer temperatures are predicted to increase further. [ABSTRACT FROM AUTHOR]

Human disturbance is of growing concern owing to the increase of human activities in natural areas. Animal responses are manifold (immediate and/or delayed, short and/or long-lasting, with numerous behaviors affected) so that comprehensive studies are few. Here, we contrasted days with low or high tourism or hunting pressures to assess direct (daytime) and indirect (nighttime) responses of 66 GPS-collared Mediterranean mouflon Ovis gmelini musimon × Ovis sp. from the Caroux-Espinouse massif (southern France) in terms of movement, habitat use and daily activity. We took advantage of the fact that both human activities occurred during different periods and with different intensities in 3 contiguous areas (among which a protected area without hunting and with limited tourism) to compare their influence on mouflon behavior. Mouflon response to tourism was limited to the area where tourism pressure was intense with a decrease in diurnal activity compensated during nighttime by an increase of nocturnal activity. Hunting had marked consequences in the two hunted areas, with a similar shift in activity between day and night, a decrease in movement sinuosity during daytime by females and an increase in nocturnal use of the best foraging habitats by males, all suggesting an increase in foraging activities during nights following disturbance. The diurnal activity of mouflon living in the protected area was also modified during hunting period, but without nocturnal compensation. These findings revealed that the impact of hunting was higher than tourism, with several components of animal behavior affected. This calls for further research on hunting side-effects in terms of disturbance, especially as it occurs during both the adverse climatic season and the breeding period. [ABSTRACT FROM AUTHOR]

ABSTRACT Studies on habitat-performance relationships that require joint data on fitness and habitat use are still scarce in long-lived species. Using data from a southern French population of Mediterranean mouflon ( Ovis gmelini musimon × Ovis sp.), we proposed an original approach for gaining information on this relationship by combining a fitness proxy (i.e., carcass mass) collected on harvested rams ( n = 257) with knowledge on habitat use obtained from other rams ( n = 13) fitted with Global Positioning System (GPS) collars. We first evaluated habitat characteristics encountered by harvested animals in hypothesized home ranges corresponding to circles centered on harvest locations. We set circle size to equal an average ram home range. We found that the carcass mass of harvested individuals decreased with aspect diversity (−16.0% from home ranges with the lowest to the highest diversity), mean slope (−9.3% between flat home ranges and steep ones), and decreasing abundance of open areas (−11.3% between the most and the least open areas). We then tested the robustness of our results by simulating circles with variable sizes and whose centers were randomly located around each harvest location. We found similar results confirming that some habitat characteristics that may be related to resource abundance and spatial structure were important drivers of ram carcass mass in this population. Finally, we showed that simulated circles of variable sizes and centered on GPS locations captured well the habitat composition of home ranges of GPS-collared rams. Combining different sources of information could hence allow drawing robust inference on key habitats in terms of performance, which is of particular interest when including a spatial component in wildlife management and conservation plans and deciding on appropriate habitat improvements. © 2014 The Wildlife Society. [ABSTRACT FROM AUTHOR]

We reviewed data on the diets of mouflon ( Mediterranean island populations Ovis gmelini musimon and introduced hybridized populations Ovis gmelini musimon × Ovis sp.) from 33 field studies (comprising 51 independent data points suitable for analysis) to detect general patterns in the botanical composition of the diet and identify ecological factors explaining its variation. We expected mouflon, generally classified as grazers, to include botanical entities other than grass in their diet, especially when they are forced to do so by low resource availability, and in certain seasons., Diet composition was investigated based on samples of rumen content and faeces. We combined these data with environmental characteristics at each site using a co-inertia analysis., As expected, grass often constituted the highest proportion in the diet (in 28 of the 51 data points) and represented on average 35% (range = 0-91%) of mouflon diet, confirming the importance of this food for the species. However, referring strictly to commonly used thresholds (>75% or >90%) shows that the classification of mouflon as grazers could be questioned. Indeed, forbs and shrubs constituted 24% (range: 0-93%) and 16% (range: 0-55%) of their diet, respectively, so that mouflon should at least be considered as variable grazers. Forbs represented a high percentage of the overall diet in the Kerguelen Archipelago, southern Indian Ocean (autumn and winter: 73%) and Teide National Park, Canary Islands, Spain (autumn and winter: 83%), whereas shrubs represented a high proportion of the overall diet in Mediterranean areas (19%)., Diet composition varied with spatio-temporal variation in forage availability (documented as habitat related or seasonal variation), confirming that mouflon are able to feed on a large variety of plants., Further investigations concerning both digestive morphology and consequences of the inclusion of browse in the diet on population dynamics of mouflon are needed to understand the persistence of this species over a wide range of habitats despite a potential mismatch between its digestive ability and its observed diet. [ABSTRACT FROM AUTHOR]

Abstract: Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N′-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a–z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases. [Copyright &y& Elsevier]

Abstract: A novel series of 2,3-diarylimidazo[1,2-a]pyridines was synthesized and evaluated for their antileishmanial activities. Four derivatives exhibited good activity against the promastigote and intracellular amastigote stages of Leishmania major, coupled with a low cytotoxicity against the HeLa human cell line. The impact of compound lipophilicity on antiparasitic activities was investigated by Log D comparison. Although LmCK1 could be the parasitic target for three compounds (13, 18, 21), the inhibition of another target is under study to explain the antileishmanial effect of the most promising compounds. [Copyright &y& Elsevier]

Abstract: A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N′-(2-cyanoaryl)-N,N-dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ɛ, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine series of compounds (4a–j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases. [Copyright &y& Elsevier]

Abstract: This Letter describes for the first time the synthesis of pyrido[2′,3′:4,5]furo[3,2-d]pyrimidines substituted by a primary or secondary amino group on position 4 of the pyrimidine ring. Application of microwave irradiation technology allowed fast and convenient procedures. [Copyright &y& Elsevier]

Abstract: The synthesis of novel functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides is described from cyanopyridine intermediates. Based on the difference in halogen reactivity, ethyl [(5-bromo-2-chloropyridin-3-yl)oxy]acetate was functionalized by a palladium-catalyzed reaction, before the cyclization to the desired furo[3,2-b]pyridines. [Copyright &y& Elsevier]

Abstract: N-Aryl-3-(indol-3-yl)propanamides were synthesized and their immunosuppressive activities were evaluated. This study highlighted the promising potency of 3-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(4-nitrophenyl)propanamide 15 which exhibited a significant inhibitory activity on murine splenocytes proliferation assay in vitro and on mice delayed-type hypersensitivity (DTH) assay in vivo. [ABSTRACT FROM AUTHOR]

Abstract: An efficient synthesis of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides is described via the formation of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile. Functionalization of the amino group at position 3 of the heterocycle will be discussed. [Copyright &y& Elsevier]

Abstract: The synthesis and study of the structure–activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC50 =39nM, 51nM and 11nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds. [Copyright &y& Elsevier]

New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative. [ABSTRACT FROM AUTHOR]

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC50 values ranging between 0.054 and 0.050 μM. In the other sub-series, eight 3-(α-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC50 value of 0.052 μM. All target compounds were further evaluated against 17α-hydroxylase/C17,20-lyase to determine their selectivity profile. [ABSTRACT FROM AUTHOR]

Abstract: Dihydropyrroloquinolines have been synthesized reacting 8-arylethynyl-1,2,3,4-tetrahydroquinolines in the presence of palladium(II) chloride catalyst. Heteroannulation has been achieved in good yields and tolerates substituents on the tetrahydroquinoline, including bromo, cyano, and ester. [Copyright &y& Elsevier]

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or α-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1 H -1,2,4-triazol-1-yl)methyl]-1 H -indole ( 3 ) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl)(1 H -1,2,4-triazol-1-yl)methyl]-3-methyl-1 H -indole ( 6 ) (60.4% inhibition). At the same concentration (100 μM) ketoconazole exerted similar inhibitory effect (70% inhibition). [ABSTRACT FROM AUTHOR]

The goal of the present study was to evaluate several azolyl-substituted indoles as new antileishmanial agents. Ten 3-(α-azolylbenzyl)indoles have been synthesized using Friedel-Crafts acylation as a key-step. All the target compounds were found to display high levels of activity when tested against Leishmania mexicana promastigotes in vitro . The most active compounds, showing an IC 50 <1 μM, were 5-bromo-1-ethyl-3-[(2,4-dichlorophenyl)(1 H -imidazol-1-yl)methyl]-1 H -indole 15 and its triazole analogue 17 . Four representative compounds 15 , 17 , 22 and, 23 were also tested against intracellular amastigotes of L. mexicana using ketoconazole and meglumine antimoniate as reference compounds, the results of which are discussed. [ABSTRACT FROM AUTHOR]

The question of how political ideology influences the perception of others is central for an understanding of relations between political groups. To characterize how political positions shape social perception, 106 students were selected according to political affinity and asked to describe political groups using either psychological or sociological qualifiers. Right-wing subjects were more likely to use psychological terms to describe political groups, whereas left-wing ones preferred sociological descriptors. Students with a right-wing position reported greatest satisfaction with psychological descriptors, while those with a left-wing position were more concerned with the relevance of qualifiers for constructing an ‘objective’ perception of reality. These observations confirm the existence of differing inclinations in the perception of social facts and social groups. Such perceptive/cognitive processes, linked to ideological patterns, seem to be inseparable from the contents to which they apply, and express the social positioning and the ideological orientations of their authors. © 1997 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Studies the various dialogs recorded in a medical assistance telephonist's workstation to determine the functional communication between two subjects a distance; Results; Discussion on the same.

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides. [ABSTRACT FROM AUTHOR]

The 27th annual GP2A (Groupement des Pharmacochimistes de l′Arc Atlantique/Group of Medicinal Chemists in the Atlantic Arc) conference took place from 21 to 23 August 2019, at the East Midlands Conference Centre (University Park, Nottingham, United Kingdom) and was hosted by the Division of Biomolecular Science and Medicinal Chemistry (BSMC), within the School of Pharmacy at the University of Nottingham. The event brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. In addition, a pre-conference workshop provided an opportunity for younger researchers to develop their theoretical knowledge in quantitative pharmacology. Abstracts of presentations by the 14 invited speakers and 6 young researchers, in addition to 41 posters, are included in this report. [ABSTRACT FROM AUTHOR]

Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(α-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17α enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom. [Copyright &y& Elsevier]

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations. [ABSTRACT FROM AUTHOR]

In polygynous ungulates, males invest time and energy to reproductive activities during the rut and this involvement is expected to increase with age due to different mating tactics in young versus adult males. In contrast, mating period is expected to be less costly for females for which late gestation and lactation are the most energetically demanding periods. However, empirical supports of these hypotheses through direct measures of reproductive effort are still limited in ungulate species, particularly in males. In addition, this general pattern may be modified in populations facing selective harvesting on adult males, where young males may experience less competition to mate and invest more energy during the rut. We investigated these hypotheses by studying the age- and sex-specific variations of kidney fat reserves from pre- to post-rut periods in a trophy-hunted population of Mediterranean mouflon (Ovis gmelini musimon × Ovis sp.), a polygynous dimorphic mountain ungulate. Females were found to build up energy from the pre-rut to the post-rut periods, most likely to face with the subsequent costs of gestation/lactation that occur few months later. Conversely, kidney fat mass strongly decreased similarly in both young and mature males, and with the same magnitude, suggesting a strong investment of males of all ages in this population. This might be related to the selective hunting pressure on mature males this population is facing with. This result supports the need for more empirical and comparative studies to better grasp the influence of trophy hunting on reproductive effort in male ungulates. [ABSTRACT FROM AUTHOR]

Hunting can be used as a tool for wildlife management, through limitation of population densities and dissuading game from using sensitive areas. The success of these approaches requires in depth knowledge of prey movement. Indeed, movement decisions of game during hunting may affect the killing success of hunters as well as the subsequent location of surviving animals. We thus investigated red deer movement responses to drive hunts and their causal factors. We studied 34 hunting events in the National Estate of Chambord (France) and thereby provided a fine-scale characterization of the immediate and delayed movement responses of red deer to drive hunts. Red deer responded to drive hunts either by immediately fleeing the hunted area, or by initially remaining before ultimately fleeing after the hunters had departed. A few hours after the hunt, all individuals were located in distant areas (> 2 kilometres) from the hunted area. Immediate flight responses were less common when drive hunts occurred in areas with dense understorey. However, neither beater/dog densities nor site familiarity influenced the immediate flight decision. Following a drive hunt, red deer remained outside the hunted areas for periods twice as long compared to periods when no hunting occurred (34 hours vs. 17 hours). Such knowledge of game movement rates in response to drive hunts may help the development of informed management policy for hunted red deer populations. [ABSTRACT FROM AUTHOR]

How large herbivores track resource quantity and quality through time has formed the core of an abundance of literature on migratory populations in recent decades. Yet, relating foraging processes and habitat selection patterns in resident populations, where spatial heterogeneity of food resources is fine‐grained and/or where the portion of edible plants (i.e. the foodscape) is low, is challenging. We addressed this issue in a mountain population of chamois Rupicapra rupicapra, an intermediate feeder, whose individuals do not migrate. We relied on a rare combination of data on habitat use of 50 GPS‐collared females and data on the quantity (biomass) and quality (phenology) of edible resources in their landscape, derived from field sampling of vegetation, remote sensing and diet (DNA barcoding). The foodscape of the chamois was composed of a low proportion of the available biomass (<18%), including relatively high‐quality plants, with low spatial covariation between plant phenology and biomass. Chamois avoided areas with a low edible biomass (where the intake rate may be too low) and focused on areas with plants at approximately the flowering stage, whatever the average plant phenological stage available. Due to this constant preference for flowering plants, home range selection ratios therefore shifted during the summer from a selection of more advanced plants in June to their avoidance in August. When the phenology scores of all plants available, rather than edible plants only, were considered, areas with relatively more advanced plants were selected all summer long. This exemplifies that, when traits from edible plants are different from those of all plants available, it is crucial to consider the actual foodscape to decipher forage and habitat selection processes. By integrating species‐specific dimensions of resources in habitat selection studies, we believe understanding of the foraging processes will be improved. [ABSTRACT FROM AUTHOR]

Most habitats are distributed heterogeneously in space, forcing animals to move according to both habitat characteristics and their needs for energy and safety. Animal space use should therefore vary according to habitat characteristics, a process known as the "functional response" in habitat selection. This response has often been tested vis-à-vis the proportion of a habitat category within areas available to individuals. Measuring sought-after resources in landscape where they are continuously distributed is a challenge and we posit here that both the mean availability of a resource and its spatial variation should be measured. Accordingly, we tested for a functional response in habitat selection according to these two descriptors of the resource available for a mountain herbivore. We hypothesized that selection should decrease with mean value of resources available and increase with its spatial variation. Based on GPS data from 50 chamois females and data on the actual foodscape (i.e. distribution of edible-only biomass in the landscape), we estimated individual selection ratio (during summer months) for biomass at the home range level, comparing edible biomass in individual home ranges and the mean and standard deviation of edible biomass in their available range. Chamois being a group-living species, available accessible ranges were shared by several individuals that formed socio-spatial groups (clusters) in the population. As expected, selection ratios increased with the standard deviation of edible resources in each cluster, but unlike our prediction, was unrelated to its mean. Selection of areas richer in resources hence did not fade away when more resources were available on average, a result that may be explained by the need for this capital breeder species to accumulate fat-reserve at a high rate during summer months. Low spatial variation could limit the selection of chamois, which highlights the importance of resource distribution in the process of habitat selection. [ABSTRACT FROM AUTHOR]

In variable environments, habitats that are rich in resources often carry a higher risk of predation. As a result, natural selection should favour individuals that balance allocation of time to foraging versus avoiding predation through an optimal decision-making process that maximizes fitness. The behavioural trade-off between resource acquisition and risk avoidance is expected to be particularly acute during gestation and lactation, when the energetic demands of reproduction peak. Here, we investigated how reproductive female roe deer adjust their foraging activity and habitat use during the birth period to manage this trade-off compared with non-reproductive juveniles, and how parturition date constrains individual tactics of risk-resource management. Activity of reproductive females more than doubled immediately following parturition, when energy demand is highest. Furthermore, compared with non-reproductive juveniles, they increased their exposure to risk by using open habitat more during daytime and ranging closer to roads. However, these post-partum modifications in behaviour were particularly pronounced in late-parturient females who adopted a more risk-prone tactic, presumably to compensate for the growth handicap of their late-born offspring. In income breeders, individuals that give birth late may be constrained to trade risk avoidance for foraging during peak allocation to reproduction, with probable consequences for individual fitness. [ABSTRACT FROM AUTHOR]

In variable environments, habitats that are rich in resources often carry a higher risk of predation. As a result, natural selection should favour individuals that balance allocation of time to foraging versus avoiding predation through an optimal decision-making process that maximizes fitness. The behavioural trade-off between resource acquisition and risk avoidance is expected to be particularly acute during gestation and lactation, when the energetic demands of reproduction peak. Here, we investigated how reproductive female roe deer adjust their foraging activity and habitat use during the birth period to manage this trade-off compared with non-reproductive juveniles, and how parturition date constrains individual tactics of risk-resource management. Activity of reproductive females more than doubled immediately following parturition, when energy demand is highest. Furthermore, compared with non-reproductive juveniles, they increased their exposure to risk by using open habitat more during daytime and ranging closer to roads. However, these post-partum modifications in behaviour were particularly pronounced in late-parturient females who adopted a more risk-prone tactic, presumably to compensate for the growth handicap of their late-born offspring. In income breeders, individuals that give birth late may be constrained to trade risk avoidance for foraging during peak allocation to reproduction, with probable consequences for individual fitness. [ABSTRACT FROM AUTHOR]

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held their 30th annual conference in August 2022 in Trinity College Dublin, Ireland. There were 9 keynote presentations, 10 early career researcher presentations and 41 poster presentations. [ABSTRACT FROM AUTHOR]

The novel precursor (II) is prepared following the procedure published for its 6-bromo analogue. [ABSTRACT FROM AUTHOR]

This paper reports the design and synthesis of a novel series of 8-arylpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3- b ]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to ( E )- N′ -(5-bromo-2-cyanothieno[2,3- b ]pyridin-3-yl)- N , N -dimethylformimidamide ( 4 ) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity. [ABSTRACT FROM AUTHOR]

Temporal partitioning of daily activities between species may promote coexistence within animal communities by reducing behavioural interference, particularly when species highly overlap in the use of space and resources. Such a strategy may be used by Alpine chamois ( Rupicapra rupicapra rupicapra) when in the presence of mouflon ( Ovis gmelini musimon × Ovis sp.), an introduced highly gregarious species with a broader ecological niche, overlapping with that of chamois. Using simultaneous monitoring of 29 Global Positioning System-collared chamois and 12 mouflon, we assessed the temporal variation in activity patterns of chamois amongst two subpopulations: one without mouflon and one with mouflon, during January and August, which are the two most extreme periods of spatial overlap of mouflon with chamois distribution. Substantial differences in activity patterns between chamois and mouflon were observed (mean 13.8 ± 10.5% in January and 10.6 ± 11.6% in August). More subtle differences appeared between both subpopulations of chamois and persisted, regardless of the spatial overlap with mouflon (3.2 ± 1.8% in January and 2.6 ± 1.5% in August), thus highlighting that there is no behavioural interference from mouflon on chamois. Our findings suggest that the temporal partitioning of daily activities between chamois and mouflon, although probably a result of species-specific adaptations to environmental conditions, may contribute to their coexistence. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 111, 621-626. [ABSTRACT FROM AUTHOR]

Abstract: The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases. [Copyright &y& Elsevier]

A useful and rapid access to libraries of N-arylbenzo[ b]furo[3,2- d]pyrimidin-4-amines ( 1) and their novel benzo[ b]thieno[3,2- d]pyrimidin-4-amine analogues ( 2) was investigated for the first time. Title compounds were obtained via microwave-accelerated condensation and of suitable anilines with N′-(2-cyanaryl)- N, N-dimethylformimidamides obtained by reaction of benzo[ b]furane and benzo[ b]thiophene precursors with N, N-dimethylformamide dimethyl acetal. This work also demonstrates that well-controlled parameters offer comfortable use of and are both safe and beneficial to the environment. Some products obtained in this article exhibit interesting in vitro antiproliferative effects. [ABSTRACT FROM AUTHOR]

Changes in vegetation phenology related to global warming are having alarming effects on the life history traits of many herbivore species. Such changes are particularly critical in alpine ecosystems, where strong climate limitations on plant growth make seasonal synchronization imperative for the growth, reproduction and survival of herbivores. However, despite the pivotal role of resource‐use strategies on the performances of such species, few studies have explicitly assessed the mechanistic impact of climate change on their diets. We aimed to fill this gap by studying the effect of spring onset on the dietary composition and quality of a medium‐size alpine herbivore while considering density‐dependent processes and age‐ and sex‐specific differences in foraging behavior. Using an exceptional, long‐term (24 years) direct individual‐based dietary monitoring of a Pyrenean chamois population (Rupicapra pyrenaica pyrenaica), we showed that ongoing earlier onsets of spring are leading to an earlier access to high‐quality forage and therefore a higher diet quality at a fixed date, without apparent changes in diet composition. We also showed that at high densities, intraspecific competition reduced diet quality by driving animals to feed more on woody plants and less on nutritious forbs and graminoids. By assessing the mechanistic effects of global warming on the dietary patterns of species at the center of trophic networks, this study is an essential step for predictive models aiming at understanding the ongoing ecosystem consequences of the global climatic crisis. [ABSTRACT FROM AUTHOR]

Abstract: An efficient method to prepare 2,3-diarylimidazo[1,2-a]pyridines is described. The procedure involves a Suzuki cross-coupling reaction followed by a direct arylation at position 3. Imidazo[1,2-a]pyridin-2-yl triflate was identified as a suitable coupling partner, permitting access to a variety of highly functionalized 2,3-diarylimidazo[1,2-a]pyridines. [Copyright &y& Elsevier]

Two 3-(α-azolylbenzyl)indoles were evaluated against Leishmania amastigotes. Both compounds proved to be very active against intracellular and axenic amastigotes. The IC 50 values of the imidazole derivative, PM17, and the triazole analogue, PM19, against L. mexicana axenic amastigotes, were 4.4 ± 0.1 and 6.4 ± 0.1 μM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 μM and PM19 had an IC 50 of 1.3 μM. In a Balb/c mice model of L. major leishmaniasis, administration of PM17 led to a clear-cut parasite burden reduction: 98.9% in the spleen, 79.0% in the liver and 49.9% in the popliteal node draining the cutaneous lesion. As anticipated, it was brought to the fore that PM17 decreases ergosterol biosynthesis leading to membrane fungal cell alterations. Moreover it was proved that this imidazole antifungal agent induces a parasite burden-correlated decrease in interleukine-4 production both in the splenocyte and the popliteal node of the mouse. [ABSTRACT FROM AUTHOR]

A three-dimensional (3-D) structure of human aromatase (CYP19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S -fadrozole and the steroidal competitive inhibitor (19 R )-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S -fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19 R )-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles of Asp309 and His480 in the aromatization of the steroid A ring. [ABSTRACT FROM AUTHOR]

The present study was designed to follow our pharma-comodulation work in the field of non-steroidal aromatase inhibitors. All target compounds 12a-h and 28a-h were tested in vitro for human placental aroma-tase inhibition, using testosterone or androstenedione the substrate for the aromatase enzyme and the IC30 and relative potency to aminoglutethimide data are included. A SAR study indicated that 3-[(4-fluorophenyl)(1 Himidazol-1-yl) methyl]-1-ethyl-2-methyl-1H-indole (28g) was a highly potent and selective aromatase inhibitor with IC50 value of 0.025 µM. 28 g was also a weak inhibitor of androstenedione synthesis. [ABSTRACT FROM AUTHOR]

The time that animals spend travelling at various speeds and the tortuosity of their movement paths are two of the many things that affect space‐use by animals. In this, high turn rates are predicted to be energetically costly, especially at high travel speeds, which implies that animals should modulate their speed according to path characteristics. When animals move so as to maximize distance and minimize metabolic energy expenditure, they travel most efficiently at the speed that gives them a minimum cost of transport (COTmin), a well‐defined point for animals that move entirely in fluid media. Theoretical considerations show though, that land animals should travel at their maximum speed to minimize COT, which they do not, instead travelling at walking pace. So, to what extent does COTmin depend on speed and turn rate and how might this relate to movement paths? We measured oxygen consumption in humans walking along paths with varied tortuosity at defined speeds to demonstrate that the energetic costs of negotiating these paths increase disproportionately with both speed and angular velocity. This resulted in the COTmin occurring at very low speeds, and these COTmin speeds reduced with increased path tortuosity and angular velocity. Logged movement data from six free‐ranging terrestrial species underpinned this because all individuals turned with greater angular velocity the slower their travel speeds across their full speed range. It seems, therefore, that land animals may strive to achieve minimum movement costs by reducing speed with increasing path variability, providing one of many possible explanations as to why speed is much lower than currently predicted based on lab measurements of mammalian locomotor performance. [ABSTRACT FROM AUTHOR]

A new 2-(α-azolylbenzyl)indole derivative exhibited high in vitro activity against 10 strains of Aspergillus fumigatus . This active compound, MT18n , had MIC of 2 μg/mL and is slightly less active than itraconazole and amphotericin B. The mechanism of action of this compound was evaluated through scanning electron microscopy, ergosterol biosynthesis inhibition and phospholipase A 2 -like activity inhibition studies. Scanning electron microscopy allowed observation of the membrane perturbations caused by MT18n and inference of a critical role of MT18n in membrane synthesis inhibition. Like other azole derivatives MT18n inhibits ergosterol biosynthesis, with a minimal inhibitory concentration of 6 μM. On the other hand, MT18n (10 μM) decreased the secreted phospholipase A 2 -like activity of Aspergillus fumigatus , an enzyme involved in the invasion process of the host. These results show the high in vitro activity of MT18n against Aspergillus fumigatus and suggest that this compound disturbs the membrane structure via ergosterol biosynthesis inhibition and exhibits phospholipase activity inhibition. [ABSTRACT FROM AUTHOR]

Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the Staphylococcus aureus 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the in silico study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC > 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent in vitro inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of −9.03 Kcal/mol and −9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against S. aureus SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells. [ABSTRACT FROM AUTHOR]