Combined effects of landscape fragmentation and sampling frequency of movement data on the assessment of landscape connectivity.

BACKGROUND: Network theory is largely applied in real-world systems to assess landscape connectivity using empirical or theoretical networks. Empirical networks are usually built from discontinuous individual movement trajectories without knowing the effect of relocation frequency on the assessment of landscape connectivity while theoretical networks generally rely on simple movement rules. We investigated the combined effects of relocation sampling frequency and landscape fragmentation on the assessment of landscape connectivity using simulated trajectories and empirical high-resolution (1 Hz) trajectories of Alpine ibex (Capra ibex). We also quantified the capacity of commonly used theoretical networks to accurately predict landscape connectivity from multiple movement processes. METHODS: We simulated forager trajectories from continuous correlated biased random walks in simulated landscapes with three levels of landscape fragmentation. High-resolution ibex trajectories were reconstructed using GPS-enabled multi-sensor biologging data and the dead-reckoning technique. For both simulated and empirical trajectories, we generated spatial networks from regularly resampled trajectories and assessed changes in their topology and information loss depending on the resampling frequency and landscape fragmentation. We finally built commonly used theoretical networks in the same landscapes and compared their predictions to actual connectivity. RESULTS: We demonstrated that an accurate assessment of landscape connectivity can be severely hampered (e.g., up to 66% of undetected visited patches and 29% of spurious links) when the relocation frequency is too coarse compared to the temporal dynamics of animal movement. However, the level of landscape fragmentation and underlying movement processes can both mitigate the effect of relocation sampling frequency. We also showed that network topologies emerging from different movement behaviours and a wide range of landscape fragmentation were complex, and that commonly used theoretical networks accurately predicted only 30-50% of landscape connectivity in such environments. CONCLUSIONS: Very high-resolution trajectories were generally necessary to accurately identify complex network topologies and avoid the generation of spurious information on landscape connectivity. New technologies providing such high-resolution datasets over long periods should thus grow in the movement ecology sphere. In addition, commonly used theoretical models should be applied with caution to the study of landscape connectivity in real-world systems as they did not perform well as predictive tools.

FRET Assays for the Identification of C. albicans HSP90-Sba1 and Human HSP90α-p23 Binding Inhibitors.

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.

Is the C-Terminal Domain an Effective and Selective Target for the Design of Hsp90 Inhibitors against Candida Yeast?

Improving the armamentarium to treat invasive candidiasis has become necessary to overcome drug resistance and the lack of alternative therapy. In the pathogenic fungus Candida albicans, the 90-kDa Heat-Shock Protein (Hsp90) has been described as a major regulator of virulence and resistance, offering a promising target. Some human Hsp90 inhibitors have shown activity against Candida spp. in vitro, but host toxicity has limited their use as antifungal drugs. The conservation of Hsp90 across all species leads to selectivity issues. To assess the potential of Hsp90 as a druggable antifungal target, the activity of nine structurally unrelated Hsp90 inhibitors with different binding domains was evaluated against a panel of Candida clinical isolates. The Hsp90 sequences from human and yeast species were aligned. Despite the degree of similarity between human and yeast N-terminal domain residues, the in vitro activities measured for the inhibitors interacting with this domain were not reproducible against all Candida species. Moreover, the inhibitors binding to the C-terminal domain (CTD) did not show any antifungal activity, with the exception of one of them. Given the greater sequence divergence in this domain, the identification of selective CTD inhibitors of fungal Hsp90 could be a promising strategy for the development of innovative antifungal drugs.

[Brucellosis in Alpine ibex: 10 years of research and expert assessments]. / La brucellose du bouquetin des Alpes - Un exemple de dix années de recherche et d'expertise.

Brucellosis due to Brucella melitensis affects domestic and wild ruminants, as well as other mammals, including humans. Despite France being officially free of bovine brucellosis since 2005, two human cases of Brucella melitensis infection in the French Alps in 2012 led to the discovery of one infected cattle herd and of one infected population of wild Alpine ibex (Capra ibex). In this review, we present the results of 10 years of research on the epidemiology of brucellosis in this population of Alpine ibex. We also discuss the insights brought by research and expert assessments on the efficacy of disease management strategies used to mitigate brucellosis in the French Alps.

Title: La brucellose du bouquetin des Alpes - Un exemple de dix années de recherche et d'expertise. Abstract: La brucellose à Brucella melitensis touche les ruminants domestiques et sauvages, ainsi que d'autres mammifères, dont les humains. Bien que la France soit officiellement indemne depuis 2005, deux cas humains reportés en Haute-Savoie en 2012 ont conduit à la découverte de l'infection dans un élevage bovin et chez les bouquetins des Alpes (Capra ibex) du massif du Bargy. Nous présentons dans cette synthèse les principales découvertes de ces dix dernières années sur le système brucellose-bouquetins. Nous discuterons également de l'apport de la recherche et de l'expertise sur l'évaluation de l'efficacité des mesures de gestion sanitaire mises en place dans le massif du Bargy pour lutter contre la brucellose.

Reproductive tactics, birth timing and the risk-resource trade-off in an income breeder.

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.

Antifungal efficacy of imidazo[1,2-a]pyrazine-based thiosemicarbazones and thiazolidinediones against Sporothrix species.

Aim: To evaluate antifungal potential of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids based on thiosemicarbazones and thiazolidinediones against pathogenic Sporothrix species. Methods: Antifungal activity of nine compounds were assessed by broth microdilution. Interactions between active compounds and itraconazole were evaluated by the checkerboard assay using non-wild-type isolates. Cytotoxicity of the compounds was determined. Results: Four C-3 substituted analogs showed antifungal activity, unrelated to thiosemicarbazone or thiazolidinedione functions. Synergistic interactions between the four compounds and itraconazole, and low toxicity on mouse fibroblast cells were observed. Activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids against Sporothrix depended on the substitution on the imidazopyrazine ring. Conclusion: Antifungal potential, overcoming itraconazole resistance and low toxicity indicate the possible use of that series of compounds in a therapeutic alternative for treatment of sporotrichosis.

Phytochemical, antileishmanial, antifungal and cytotoxic profiles of Thymelaea tartonraira (L.) All. extracts.

Extracts from leaves and stems of Thymelaea tartonraira (L.) All. growing in Tunisia were characterised for the presence of flavonoids and phenolic acids by LC-ESI-MS analysis. Twelve flavonoids and ten phenolic acids were detected for the first time in the aerial parts of this plant species, the most abundant compounds being gallic acid, kaempferol, catechin, chlorogenic acid, naringenin and acacetin. The extracts were subjected to in vitro antileishmanial, antifungal and cytotoxic assays, showing promising antileishmanial activity for the E6 dichloromethane extract from the stems (IC50 values of 1.12 ± 0.50 and 5.41 ± 1.84 µg/mL on L. donovani axenic and intramacrophagic amastigotes, respectively) at the level of the reference drug miltefosine for axenic model. No antifungal activity was observed against Candida albicans (CAAL) and Aspergillus fumigatus (ASFU) strains, with the exception of the E6 dichloromethane extract (IC50 value of 25.28 ± 4.89 µg/mL on CAAL93 strain). Low toxicity was also highlighted against macrophages Raw 264.7 cells. These promising results point out Thymelaea tartonraira (L.) All. extracts as a valuable source of new natural products to combat leishmaniasis.

30th Annual GP2A Medicinal Chemistry Conference.

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.

New Specific α-Glucosidase Inhibitor Flavonoid from Thymelaea tartonraira Leaves: Structure Elucidation, Biological and Molecular Docking Studies.

The phytochemical investigation of Thymelaea tartonraira leaves led to the isolation and characterization of six compounds, including one new flavonoid glycoside identified as hypolaetin 8-O-ß-D-galactopyranoside (4) along with five known compounds, daphnoretin (1), triumbelletin (2), genkwanin (3), tiliroside (5) and yuankanin (6). Their structures were established based on spectroscopic methods, such as UV, IR, NMR, and HR-ESI-MS. Triumbelletin (2) and tiliroside (5) were isolated for the first time from T. tartonraira leaves. The antioxidant property of all isolated compounds was tested based on DPPH, FRAP and total antioxidant capacity assays. Compound 4 displayed an antioxidant potency more interesting than vitamin C with an IC50 =15.00±0.50 µg/ml, followed by compound 5. Furthermore, the both compounds 4 and 5 were tested for their α-amylase inhibitory activity in-vitro. Compound 4 displayed higher potency to inhibit α-amylase, with an IC50 =46.49±2.32 µg/ml, than compound 5, with an IC50 =184.2±9.2 µg/ml, while the reference compound acarbose presented the highest potency to inhibit α-amylase with an IC50 =0.44±0.022 µg/ml. Compound 4 displayed a strong inhibitory ability of α-glucosidase activity approximately twice more than the reference compound, acarbose, with IC50 values of 60.00±3.00 and 125.00±6.25 µg/ml, respectively. Thus, compound 4 exhibited a specific inhibitory activity for α-glucosidase. The molecular docking studies have supported our findings and suggested that compound 4 has been involved in various binding interactions within the active site of both enzymes α-amylase and α-glucosidase.

Effects of Acylhydrazone Derivatives on Experimental Pulmonary Inflammation by Chemical Sensitization.

BACKGROUND: Chronic lung diseases are characterized by airway inflammation and remodelling of the lung parenchyma that triggers considerable impairment of respiratory function. OBJECTIVE: In this study, two compounds belonging to the N-acylhydrazone class were evaluated, aiming to identify new therapeutic agents for pulmonary inflammatory diseases. MATERIALS AND METHODS: The acute toxicity of 2-cyano-N'-(3-ethoxy-4-hydroxybenzylidene)- acetohydrazide (JR-12) and N'-benzylidene-2-cyano-3-phenylacrylohydrazide (JR09-Bz) was evaluated. Afterwards, they were tested in models of ovalbumin (OVA)-induced allergic asthma and pleurisy, bleomycin-induced pulmonary fibrosis, in addition to mucolytic activity. RESULTS AND DISCUSSION: The compounds did not show toxicity at the dose of 2,000 mg/kg, and no animal died. On OVA-induced pleurisy, animals treated with JR-12 or JR09-Bz at a dose of 10 mg/kg (orally) showed significant inhibition of the leukocyte infiltrate in the bronchoalveolar lavage by 62.5% and 61.5%, respectively, compared to the control group. The compounds JR-12 and JR09-Bz were also active in blocking the allergic asthmatic response triggered by OVA, reducing the leukocyte infiltrate by 73.1% and 69.8%, respectively. Histopathological changes and mast cell migration in treated animals with JR-12 or JR09-Bz were similar to treatment with the reference drugs dexamethasone and montelukast. JR-12 and JR09-Bz also reversed airway remodeling in animals on the bleomycin-induced fibrosis model compared to the control group. Furthermore, it was observed that N-arylhydrazone derivatives showed expectorant and mucolytic activities, increasing mucus secretion by 45.6% and 63.8% for JR-12 and JR09-Bz, respectively. CONCLUSION: Together, the results show that JR-12 and JR09-Bz showed promising activity against airway inflammation, as well as low toxicity.

Interacting lethal and nonlethal human activities shape complex risk tolerance behaviors in a mountain herbivore.

Animals perceive human activities as risky and generally respond with fear-induced proactive behaviors to buffer the circadian patterns of lethal and nonlethal disturbances, such as diel migrations (DMs) between risky places during safe nighttime and safer places during risky daytime. However, such responses potentially incur costs through movement or reduced foraging time, so individuals should adjust their tolerance when human activities are harmless, through habituation. Yet this is a challenging cognitive task when lethal and nonlethal risks co-occur, forming complex landscapes of fear. The consequences of this human-induced complexity have, however, rarely been assessed. We studied the individual DM dynamics of chamois (Rupicapra rupicapra rupicapra), 89 GPS-tracked individual-years, from/to trails in the French Alps in areas with co-occurring lethal (hunting) and nonlethal (hiking and skiing) disturbances, with different intensities across seasons. We developed a conceptual framework relying on the risk-disturbance hypothesis and habituation to predict tolerance adjustments of chamois under various disturbance contexts and across contrasted seasonal periods. Based on spatial and statistical analyses combining periodograms and multinomial logistic models, we found that DM in relation to distance to a trail was a consistent response by chamois (~85% of individuals) to avoid human disturbance during daytime, especially during the hiking and hunting periods. Such behavior revealed a low tolerance of most chamois to human activities, although there was considerable interindividual heterogeneity in DM. Interestingly, there was an increased tolerance among the most disturbed diel migrants, potentially through habituation, with chamois performing shorter DMs in areas highly disturbed by hikers. Crucially, chamois that were most human-habituated during the hiking period remained more tolerant in the subsequent harvesting period, which could increase their risk of being harvested. In contrast, individuals less tolerant to hiking performed longer DMs when hunting risk increased, and compared to hiking, hunting exacerbated the threshold distance to trails triggering DMs. No carryover effect of hunting beyond the hunting period was observed. In conclusion, complex human-induced landscapes of fear with co-occurring disturbances by nature-based tourism and hunting may shape unexpected patterns of tolerance to human activities, whereby animal tolerance could become potentially deleterious for individual survival.

Combining seroprevalence and capture-mark-recapture data to estimate the force of infection of brucellosis in a managed population of Alpine ibex.

In wildlife, epidemiological data are often collected using cross-sectional surveys and antibody tests, and seroprevalence is the most common measure used to monitor the transmission dynamics of infectious diseases. On the contrary, the force of infection, a measure of transmission intensity that can help understand epidemiological dynamics and monitor management interventions, remains rarely used. The force of infection can be derived from age-stratified cross-sectional serological data, or from longitudinal data (although less frequently available in wildlife populations). Here, we combined seroprevalence and capture-mark-recapture data to estimate the force of infection of brucellosis in an Alpine ibex (Capra ibex) population monitored from 2012 to 2018. Because the seroprevalence of brucellosis was 38% in this population in 2012, managers conducted two culling operations in 2013 and 2015, as well as captures every year since 2012, where seronegative individuals were marked and released, and seropositive individuals were removed. We obtained two estimates of the force of infection and its changes across time, by fitting (i) a catalytic model to age-seroprevalence data obtained from unmarked animals (cross-sectional), and (ii) a survival model to event time data obtained from recaptures of marked animals (longitudinal). Using both types of data allowed us to make robust inference about the temporal dynamics of the force of infection: indeed, there was evidence for a decrease in the force of infection between mid-2014 and late 2015 in both datasets. The force of infection was estimated to be reduced from 0.115 year-1 [0.074-0.160] to 0.016 year-1 [0.001-0.057]. These results confirm that transmission intensity decreased during the study period, probably due to management interventions and natural changes in infection dynamics. Estimating the force of infection could therefore be a valuable complement to classical seroprevalence analyses to monitor the dynamics of wildlife diseases, especially in the context of ongoing disease management interventions.

Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice.

BACKGROUND: In a study recently published by our research group, the isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. OBJECTIVE: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. METHODS: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. RESULTS: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. CONCLUSION: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

Positive effect of spring advance on the diet quality of an alpine herbivore.

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.

On this side of the fence: Functional responses to linear landscape features shape the home range of large herbivores.

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.

29th Annual GP2A Medicinal Chemistry Conference.

The 29th Annual GP2A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry.

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases.

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

Targeted strategies for the management of wildlife diseases: the case of brucellosis in Alpine ibex.

The management of infectious diseases in wildlife reservoirs is challenging and faces several limitations. However, detailed knowledge of host-pathogen systems often reveal heterogeneity among the hosts' contribution to transmission. Management strategies targeting specific classes of individuals and/or areas, having a particular role in transmission, could be more effective and more acceptable than population-wide interventions. In the wild population of Alpine ibex (Capra ibex-a protected species) of the Bargy massif (French Alps), females transmit brucellosis (Brucella melitensis) infection in ~90% of cases, and most transmissions occur in the central spatial units ("core area"). Therefore, we expanded an individual-based model, developed in a previous study, to test whether strategies targeting females or the core area, or both, would be more effective. We simulated the relative efficacy of realistic strategies for the studied population, combining test-and-remove (euthanasia of captured animals with seropositive test results) and partial culling of unmarked animals. Targeting females or the core area was more effective than untargeted management options, and strategies targeting both were even more effective. Interestingly, the number of ibex euthanized and culled in targeted strategies were lower than in untargeted ones, thus decreasing the conservation costs while increasing the sanitary benefits. Although there was no silver bullet for the management of brucellosis in the studied population, targeted strategies offered a wide range of promising refinements to classical sanitary measures. We therefore encourage to look for heterogeneity in other wildlife diseases and to evaluate potential strategies for improving management in terms of efficacy but also acceptability.

Synthesis, anticancer activity and mechanism of action of new phthalimido-1,3-thiazole derivatives.

In this work, 22 new compounds were obtained and evaluated for their cytotoxic activity on peripheral blood mononuclear cells (PBMC) and eight different tumor cell lines. All compounds displayed IC50 values above 100 µM when assayed against PBMCs. The cytotoxic assays in tumor cell lines revealed that sub-series of phthalimido-bis-1,3-thiazoles (5a-f) exhibited the best anti-tumor activity profile, presenting viability values below 59 %. As a result, the IC50 value was calculated for compounds 5a-f and 4c, and compounds 5b and 5e were selected for further assays due to their best IC50s. Considering the results presented by the sub-series 5a-f, the importance of the 1,3-thiazole ring in improving the anti-tumor activity was pointed out. Together, the results highlighted the anti-tumor activity of phthalimido-bis-1,3-thiazole derivatives.

In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition.

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.