Towards the synthesis of the salarins, marine macrolides from the sponge Fascaplysinopsis sp.

Die Salarine A–J aus dem Meeresschwamm Fascaplysinopsis sp. bilden eine einzigartige Familie von 17-gliedrigen Makrolaktonen und wurden 2008 erstmals von Kashman et al. isoliert. Strukturell charakteristisch für die Salarine ist, dass die meisten eine dreifach substituierte Oxazoleinheit oder eine Trisacylaminfunktion aufweisen, welche in den Makrozyklus integriert sind. Salarin C zeigt vielversprechende zytotoxische Eigenschaften gegen menschliche Leukämiezelllinien. Salarin C unterscheidet sich charakteristisch von Salarin A durch einen anstelle der Trisacylamin-Funktion in den Makrozyklus eingebetteten Oxazolring. Kashman et al. fanden, dass Salarin C unter Einwirkung von Licht und Luft in das Trisacylamin Salarin A umgewandelt wird. In dieser Arbeit wird die modulare Synthese des Makrozyklus von Salarin C vorgestellt, wobei die Epoxide durch Alkeneinheiten ersetzt wurden. Oxidation mit Singulett-Sauerstoff ermöglichte die Überführung in den Makrozyklus von Salarin A. Der Makrozyklus wurde aus zwei Bausteinen, einem sekundären Alkohol mit terminalem Alken und einer Carbonsäure mit ebenfalls einem terminalen Alken, aufgebaut. Die stereoselektive Synthese des Alkohol-Bausteins, der alle stereogenen Zentren des Makrozyklus aufwies, erfolgte in elf Stufen ausgehend von einem Glyceraldehyd-Derivat. Zunächst erfolgte eine titanvermittelte Addition eines Lithiumacetylids an den Aldehyd, wobei das Felkin Addukt in einem Diastereomerenüberschuss von 85% gebildet wurde. Überführung in das (Z)-Alken mittels Lindlar-Katalysator und Einführung orthogonaler Schutzgruppen ermöglichten es den sekundären Alkohol-Baustein zu erhalten. Der Carbonsäure-Baustein, welcher zudem die Oxazolfunktion beinhaltete, wurde über 14 Stufen ausgehend von 2-Butylsulfanyl-5-iodoxazol aufgebaut. Zunächst wurde mittels Halogen-Dance-Reaktion das 2-Butylsulfanyl-4-iod-5-methyloxazol synthetisiert, welches in 4-Position durch Sonogashira-Reaktion mit Propargylalkohol und in 2-Position durch eine nukleophile Substitution mit einer Organolithiumspezies erweitert wurde. Aus dem Propargylalkohol wurde die Carbonsäure aufgebaut. Die beiden Bausteine wurden zunächst mittels Veresterung über ein Carbonsäurechlorid in den Ringschlussvorläufer überführt, um eine DMAP-induzierte Isomerisierung des Diensystems zu vermeiden. Der Ringschluss erfolgte anschließend mittels (E)-selektiver Ringschlussmetathese mit dem Grubbs II-Katalysator und ergab den Makrozyklus von Salarin C.The salarins A–J are part of a unique group of 17-membered macrolactones and were first isolated in 2008 from the Madagascan sponge Fascaplysinopsis sp. by Kashman and co-workers. Most salarins contain either a trisubstituted oxazole or a trisacylamine moiety, which is embedded in the macrocycle. The nitrogenous macrolide salarin C exhibits promising biological activity against human leucemia cell lines on a nanomolar scale, including apoptosis and DNA damage. Salarin C and salarin A differ characteristically as salarin A contains a trisacylamine moiety, whereas salarin C shows a trisubstituted oxazole ring embedded in the macrocycle. Kashman et al. discovered that salarin C is converted to the trisacylamine salarin A on exposure to air and oxygen, presumably via cycloaddition of oxygen to the oxazole. In this work the modular synthesis of the macrocyclic core of salarin C is described, with the two epoxides being replaced by alkene moieties. Oxidation with singlet oxygen provided the transformation to the macrocycle of salarin A. The macrocycle was built from two fragments, a secondary alcohol containing a terminal alkene and a carboxylic acid, also containing a terminal alkene. The stereoselective synthesis of the alcohol building block, containing all stereocenters of the later macrocycle, was accomplished in eleven steps starting from a glyceraldehyde derivative. It started with a titanium-assisted nucleophilic alkynylation of the aldehyde, affording the Felkin adduct in a diastereomeric excess of 85%. Hydrogenation of the alkyne to the (Z)-alkene by Lindlar catalyst was followed by a series of protection and deprotection steps to afford the secondary alcohol building block. The carboxylic acid building block, containing the oxazol moiety, was synthesized in 14 steps starting from 2-butylsulfanyl-5-iodooxazole. Halogen dance reaction provided 2-butylsulfanyl-4-iodo-5-methyloxazole which was elongated in 4-position by Sonogashira coupling with propargyl alcohol and in 2-position by nucleophilic substitution with an organolithium species to give the methyl pentene motif. The carboxylic acid was established by transformation of the coupled propargyl alcohol. The two building blocks were combined by esterification via the acid chloride, to avoid an DMAP-induced isomerization of the diene. With the cyclization precursor in hands the macrocycle of Salarin C was set up by (E)-selective ring-closing metathesis with Grubbs II catalyst

Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Insect bite hypersensitivity (IBH) is the most common allergic skin disease of horses. It is caused by insect bites of the Culicoides spp. which mediate a type I/IVb allergy with strong involvement of eosinophil cells. No specific treatment option is available so far. One concept could be the use of a therapeutic antibody targeting equine interleukin 5, the main activator and regulator of eosinophils. Therefore, antibodies were selected by phage display using the naïve human antibody gene libraries HAL9/10, tested in a cellular in vitro inhibition assay and subjected to an in vitro affinity maturation. In total, 28 antibodies were selected by phage display out of which eleven have been found to be inhibiting in the final format as chimeric immunoglobulin G with equine constant domains. The two most promising candidates were further improved by in vitro affinity maturation up to factor 2.5 regarding their binding activity and up to factor 2.0 regarding their inhibition effect. The final antibody named NOL226-2-D10 showed a strong inhibition of the interleukin 5 binding to its receptor (IC50 = 4 nM). Furthermore, a nanomolar binding activity (EC50 = 8.8 nM), stable behavior and satisfactory producibility were demonstrated. This antibody is an excellent candidate for in vivo studies for the treatment of equine IBH

The Contribution of Desert-Dwelling Bats to Pest Control in Hyper-Arid Date Agriculture

This is the final version. Available on open access from MDPI via the DOI in this recordData Availability Statement: Data is part of bigger unpublished data sets which will be available once published.Over 40% of the Earth’s surface has been converted to agricultural use and agroecosystems have become important habitats for wildlife. In arid regions, intensive agriculture creates artificial oasis-like habitats due to their high irrigation inputs. Date production is one of the primary agricultural practices in the deserts of the Middle East and North Africa. Insectivorous bats are known to use agricultural areas, but the role of date plantations as their foraging habits and the importance of insectivorous bats as date bio-pest control agents are still unknown. We assessed the role of date plantations as foraging habitats for local desert bat species by acoustically recording bat activity in conventional and organic date plantations in the southern Arava Valley, Israel. In addition, we captured bats in the plantations and collected feces for DNA metabarcoding analysis to investigate the presence of pest species in their diets. We found that 12 out of the 16 known species of bats in this region frequently used both conventional and organic date plantations as foraging habitats. Species richness was highest in the organic plantation with complex ground vegetation cover. Foraging activity was not affected by plantation type or management. However, bat species richness and activity increased in all plantations during summer date harvesting. Molecular analysis confirmed that bats feed on a variety of important date pests, but the particular pests consumed and the extent of consumption varied among bat species. Our results highlight a win–win situation, whereby date plantations are an important foraging habitat for desert bats, while bats provide bio-pest control services that benefit the date plantations. Therefore, date farmers interested in bio-pest control should manage their plantations to support local desert bat populations.CA in IsraelKKL-JNFIsrael Ministry of Agriculture and Rural Developmen

Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Insect bite hypersensitivity (IBH) is the most common allergic skin disease of horses. It is caused by insect bites of the Culicoides spp. which mediate a type I/IVb allergy with strong involvement of eosinophil cells. No specific treatment option is available so far. One concept could be the use of a therapeutic antibody targeting equine interleukin 5, the main activator and regulator of eosinophils. Therefore, antibodies were selected by phage display using the naïve human antibody gene libraries HAL9/10, tested in a cellular in vitro inhibition assay and subjected to an in vitro affinity maturation. In total, 28 antibodies were selected by phage display out of which eleven have been found to be inhibiting in the final format as chimeric immunoglobulin G with equine constant domains. The two most promising candidates were further improved by in vitro affinity maturation up to factor 2.5 regarding their binding activity and up to factor 2.0 regarding their inhibition effect. The final antibody named NOL226-2-D10 showed a strong inhibition of the interleukin 5 binding to its receptor (IC50 = 4 nM). Furthermore, a nanomolar binding activity (EC50 = 8.8 nM), stable behavior and satisfactory producibility were demonstrated. This antibody is an excellent candidate for in vivo studies for the treatment of equine IBH

From food to pest: Conversion factors determine switches between ecosystem services and disservices

Ecosystem research focuses on goods and services, thereby ascribing beneficial values to the ecosystems. Depending on the context, however, outputs from ecosystems can be both positive and negative. We examined how provisioning services of wild animals and plants can switch between being services and disservices. We studied agricultural communities in Laos to illustrate when and why these switches take place. Government restrictions on land use combined with economic and cultural changes have created perceptions of rodents and plants as problem species in some communities. In other communities that are maintaining shifting cultivation practices, the very same taxa were perceived as beneficial. We propose conversion factors that in a given context can determine where an individual taxon is located along a spectrum from ecosystem service to disservice, when, and for whom. We argue that the omission of disservices in ecosystem service accounts may lead governments to direct investments at inappropriate targets

Ecosystem services and disservices provided by small rodents in arable fields: effects of local and landscape management

1. In agriculture, both valuable ecosystem services and unwanted ecosystem disservices can be produced by the same organism group. For example, small rodents can provide biological control through weed seed consumption but may also act as pests, causing crop damage. 2. We studied the hypothesised causal relationships between ecosystem services (removal of weed seeds) and disservices (removal of wheat and crop damage) derived by small rodents (voles and mice) at multiple spatial scales. At the landscape scale, we studied the effects of landscape compositional and configurational heterogeneity along the former inner German border in east and west Germany on the abundance of voles and mice and their related ecosystem services and disservices. At the local scale, we studied how this abundance and ecosystem functions are affected by management intensity (organic vs. conventional winter wheat), associated differences in crop characteristics and edge effects. 3. Linear mixed effects models and path analysis show that voles drive ecosystem disservices, but not ecosystem services, in agricultural fields. Daily wheat seed removal by voles was influenced by increasing wheat height and was almost three times higher than weed seed removal, which was not related to local or landscape-scale effects. 4. Abundance of voles and associated crop damage decreased with lower crop density and higher wheat height, which were associated with organic farming. Abundance of voles and crop damage were highest in conventional fields in west Germany. 5. Synthesis and applications. As the ecosystem disservice of wheat seed consumption by voles and mice must be considered mainly during crop sowing, management before harvest should focus on decreasing the pest potential of voles’ but not mice. Our results suggest that densities of voles and their ecosystem disservices could be reduced by having fields with low crop density and high wheat height, practices associated with organic farming. Surrounding landscapes with low compositional and configurational heterogeneity could further reduce voles’ pest potential, but with probable negative effects on farmland biodiversity

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies

How Fast Does the Steppe Eagle Population Decline? Survey Results from Eilat, Israel

The world Steppe Eagle (Aquila nipalensis) population is considered Endangered and is rapidly declining across most of it range. Eilat, in southernIsrael, is a bottleneck for this species on its migration route fromAfrica in spring. We conducted a series of surveys, counting the passing Steppe Eagles in springs 2015 to 2018 and collecting data about the age of the passing birds. We then compared our data with the Steppe Eagle data collected during four springs between 1977 and 1988. We did not find a significant decline in Steppe Eagle numbers passing Eilat on their spring migration between the two data sets. This implies that the overwintering sites in Africa and the migration flyway to and fromAfrica are relatively safe for the Steppe Eagles. We furthermore found that 75% of the eagles passing are adults and that their main passage is during the third week of February. This information helps to adjust conservation efforts

Schaeckermann_et_al_data_JAPPL

Data used for the publication "Natural habitat does not mediate vertebrate seed predation as an ecosystem dis-service to agriculture". Data for the different analyses appears on the first three tables, the fourth table offers explanations

Data from: Natural habitat does not mediate vertebrate seed predation as an ecosystem dis-service to agriculture

1. Spillover of beneficial organisms from natural habitats to croplands can improve agro-ecosystem services, but wildlife can also negatively influence agricultural production. When managing agricultural landscapes to conserve biodiversity, we need to understand if the availability of natural habitats increases ecosystem dis-services such as vertebrate seed predation to avoid risking higher costs than benefits. 2. We studied whether vertebrates and their impact in crop seed predation are related to the percentage of natural (Chaparral) and semi-natural habitat (planted forest with native and exotic trees) in an agricultural landscape of Israel. We selected 20 almond and 20 sunflower study sites within a landscape with varying percentages of natural (0–61%) and semi-natural (0–70%) habitats within a 1000-m radius of their surroundings. We observed birds, trapped rodents (in almond), counted seeds and noted feeding marks to obtain seed predation rates, at each site. Within the almond crops, we physically excluded birds, rodents and both to determine their relative and combined influence on seed predation. 3. Neither vertebrate abundance nor species richness was influenced by the percentage of natural habitat. However, bird species richness increased with increasing percentage of semi-natural habitat. 4. Seed predation across both crops was not influenced by natural or semi-natural habitat but increased significantly with increasing abundance and species richness of birds. This was also reflected by the exclusions of birds, vertebrates and both to the almond crop, leading to lowest seed predation when both groups were excluded. 5. Synthesis and applications. Natural or semi-natural habitat did not influence the agro-ecosystem dis-service of seed predation by birds and rodents. Policymakers should consider promoting agri-environment schemes that include the conservation of natural habitats and the management of semi-natural habitats adjacent to cropland to enhance agro-ecosystem services meditated by beneficial organisms like natural pest enemies and pollinators without fearing increased vertebrate seed predation. In order to provide more detailed management recommendations tackling the reduction of vertebrate dis-services their feeding behaviour, metabolic needs, behaviour patterns and local abundances should be taken into account