Covalent targeting of non-cysteine residues in PI4KIIIß.

The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIß is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.

Machine and deep learning approaches to understand and predict habitat suitability for seabird breeding.

The way animals select their breeding habitat may have great impacts on individual fitness. This complex process depends on the integration of information on various environmental factors, over a wide range of spatiotemporal scales. For seabirds, breeding habitat selection integrates both land and sea features over several spatial scales. Seabirds explore these features prior to breeding, assessing habitats' quality. However, the information-gathering and decision-making process by seabirds when choosing a breeding habitat remains poorly understood. We compiled 49 historical records of larids colonies in Cuba from 1980 to 2020. Then, we predicted potentially suitable breeding sites for larids and assessed their breeding macrohabitat selection, using deep and machine learning algorithms respectively. Using a convolutional neural network and Landsat satellite images we predicted the suitability for nesting of non-monitored sites of this archipelago. Furthermore, we assessed the relative contribution of 18 land- and marine-based environmental covariates describing macrohabitats at three spatial scales (i.e. 10, 50 and 100 km) using random forests. Convolutional neural network exhibited good performance at training, validation and test (F1-scores >85%). Sites with higher habitat suitability (p > .75) covered 20.3% of the predicting area. Larids breeding macrohabitats were sites relatively close to main islands, featuring sparse vegetation cover and high chlorophyll-a concentration at sea in 50 and 100 km around colonies. Lower sea surface temperature at larger spatial scales was determinant to distinguish the breeding from non-breeding sites. A more comprehensive understanding of the seabird breeding macrohabitats selection can be reached from the complementary use of convolutional neural networks and random forest models. Our analysis provides crucial knowledge in tropical regions that lack complete and regular monitoring of seabirds' breeding sites.

European Medicinal Chemistry Leaders in Industry (EMCL) - On the Status and Future of Medicinal Chemistry Research in Europe.

The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.

From the light blue sky to the dark deep sea: Trophic and resource partitioning between epipelagic and mesopelagic layers in a tropical oceanic ecosystem.

The connection between epipelagic and deep-sea mesopelagic realms controls a variety of ecosystem processes including oceanic carbon storage and the provision of harvestable fish stocks. So far, these two layers have been mostly addressed in isolation and the ways they connect remain poorly understood. Furthermore, both systems are affected by climate change, exploitation of resources, and increasing pervasion of pollutants. Here we use bulk isotopes of δ13C and δ15N of 60 ecosystem components to evaluate the trophic linkage between epipelagic and mesopelagic ecosystems in warm oligotrophic waters. Additionally, we we conducted a comparison of isotopic niche sizes and overlaps across multiple species to evaluate how environmental gradients between epipelagic and mesopelagic ecosystems shape ecological patterns of resource use and competition between species. Our database comprises siphonophores, crustaceans, cephalopods, salpas, fishes, and seabirds. It also includes five zooplankton size classes, two groups of fish larvae, and particulate organic matter collected at different depths. Through this wide taxonomic and trophic variety of epipelagic and mesopelagic species, we show that pelagic species access resources originating from different food sources, mostly autotrophic-based (epipelagics) and microbial heterotrophic-based (mesopelagics). This leads to a sharp trophic dissimilarity between vertical layers. Additionally, we show that trophic specialization increases in deep-sea species and argue that food availability and environmental stability are among the main drivers of this pattern. Finally, we discuss how the ecological traits of pelagic species highlighted in this study can respond to human impacts and increase their vulnerability in the Anthropocene.

Deep inference of seabird dives from GPS-only records: Performance and generalization properties.

At-sea behaviour of seabirds have received significant attention in ecology over the last decades as it is a key process in the ecology and fate of these populations. It is also, through the position of top predator that these species often occupy, a relevant and integrative indicator of the dynamics of the marine ecosystems they rely on. Seabird trajectories are recorded through the deployment of GPS, and a variety of statistical approaches have been tested to infer probable behaviours from these location data. Recently, deep learning tools have shown promising results for the segmentation and classification of animal behaviour from trajectory data. Yet, these approaches have not been widely used and investigation is still needed to identify optimal network architecture and to demonstrate their generalization properties. From a database of about 300 foraging trajectories derived from GPS data deployed simultaneously with pressure sensors for the identification of dives, this work has benchmarked deep neural network architectures trained in a supervised manner for the prediction of dives from trajectory data. It first confirms that deep learning allows better dive prediction than usual methods such as Hidden Markov Models. It also demonstrates the generalization properties of the trained networks for inferring dives distribution for seabirds from other colonies and ecosystems. In particular, convolutional networks trained on Peruvian boobies from a specific colony show great ability to predict dives of boobies from other colonies and from distinct ecosystems. We further investigate accross-species generalization using a transfer learning strategy known as 'fine-tuning'. Starting from a convolutional network pre-trained on Guanay cormorant data reduced by two the size of the dataset needed to accurately predict dives in a tropical booby from Brazil. We believe that the networks trained in this study will provide relevant starting point for future fine-tuning works for seabird trajectory segmentation.

Mercury concentrations, biomagnification and isotopic discrimination factors in two seabird species from the Humboldt Current ecosystem.

Assessing mercury (Hg) biomagnification requires the description of prey-predator relationships, for each species and ecosystem, usually based on carbon and nitrogen isotope analyses. Here, we analyzed two seabirds from the Humboldt Current ecosystem, the Guanay cormorant (Phalacrocorax bougainvillii) and the Peruvian booby (Sula variegata), as well as their main prey, the Peruvian anchovy (Engraulis ringens). We reported Hg concentrations, Hg biomagnification (BMF) and isotopic discrimination factors (Δ13C and Δ15N) in seabird whole blood. BMFs and Δ13C in our study (on wild birds where diet was not controlled) were similar to other piscivorous seabirds previously studied in captive settings, but Δ15N were lower than most captive experiments. We observed lower Hg concentrations in Humboldt seabirds compared to other oligotrophic ecosystems, possibly due to Hg biodilution in the high biomass of the first trophic levels. This work calls for a better characterization of Hg trophic dynamics in productive upwelling ecosystems.

Ecological trap for seabirds due to the contamination caused by the Fundão dam collapse, Brazil.

Human-induced rapid environmental changes can disrupt habitat quality in the short term. A decrease in quality of habitats associated with preference for these over other available higher quality is referred as ecological trap. In 2015, the Fundão dam containing iron mining tailings, eastern Brazil, collapsed and released about 50 million cubic meters of metal-rich mud composed by Fe, As, Cd, Hg, Pb in three rivers and the adjacent continental shelf. The area is a foraging site for dozens of seabird and shorebird species. In this study, we used a dataset from before and after Fundão dam collapse containing information on at-sea distribution during foraging activities (biologging), dietary aspects (stable isotopes), and trace elements concentration in feathers and blood from three seabird species known to use the area as foraging site: Phaethon aethereus, Sula leucogaster, and Pterodroma arminjoniana. In general, a substantial change in foraging strategies was not detected, as seabirds remain using areas and food resources similar to those used before the dam collapse. However, concentration of non-essential elements increased (e.g., Cd and As) while essential elements decreased (e.g., Mn and Zn), suggesting that the prey are contaminated by trace elements from tailings. This scenario represents evidence of an ecological trap as seabirds did not change habitat use, even though it had its quality reduced by contamination. The sinking-resuspension dynamics of tailings deposited on the continental shelf can temporally increase seabird exposure to contaminants, which can promote deleterious effects on populations using the region as foraging sites in medium and long terms.

ENSO Climate Forcing of the Marine Mercury Cycle in the Peruvian Upwelling Zone Does Not Affect Methylmercury Levels of Marine Avian Top Predators.

Climate change is expected to affect marine mercury (Hg) biogeochemistry and biomagnification. Recent modeling work suggested that ocean warming increases methylmercury (MeHg) levels in fish. Here, we studied the influence of El Niño Southern Oscillations (ENSO) on Hg concentrations and stable isotopes in time series of seabird blood from the Peruvian upwelling and oxygen minimum zone. Between 2009 and 2016, La Niña (2011) and El Niño conditions (2015-2016) were accompanied by sea surface temperature anomalies up to 3 °C, oxycline depth change (20-100 m), and strong primary production gradients. Seabird Hg levels were stable and did not co-vary significantly with oceanographic parameters, nor with anchovy biomass, the primary dietary source to seabirds (90%). In contrast, seabird Δ199Hg, proxy for marine photochemical MeHg breakdown, and δ15N showed strong interannual variability (up to 0.8 and 3‰, respectively) and sharply decreased during El Niño. We suggest that lower Δ199Hg during El Niño represents reduced MeHg photodegradation due to the deepening of the oxycline. This process was balanced by equally reduced Hg methylation due to reduced productivity, carbon export, and remineralization. The non-dependence of seabird MeHg levels on strong ENSO variability suggests that marine predator MeHg levels may not be as sensitive to climate change as is currently thought.

Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,5-bicyclic heterocycles.

Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.

UV-Induced 1,3,4-Oxadiazole Formation from 5-Substituted Tetrazoles and Carboxylic Acids in Flow.

A range of 1,3,4-oxadiazoles have been synthesized using a UV-B activated flow approach starting from carboxylic acids and 5-substituted tetrazoles. The application of UV light represents an attractive alternative to the traditional thermolytic approach and has demonstrated comparable efficiency and versatility, with a diverse substrate scope, including the incorporation of highly substituted amino acids.

"Too Big To Ignore": A feasibility analysis of detecting fishing events in Gabonese small-scale fisheries.

In many developing countries, small-scale fisheries provide employment and important food security for local populations. To support resource management, the description of the spatiotemporal extent of fisheries is necessary, but often poorly understood due to the diffuse nature of effort, operated from numerous small wooden vessels. Here, in Gabon, Central Africa, we applied Hidden Markov Models to detect fishing patterns in seven different fisheries (with different gears) from GPS data. Models were compared to information collected by on-board observers (7 trips) and, at a larger scale, to a visual interpretation method (99 trips). Models utilizing different sampling resolutions of GPS acquisition were also tested. Model prediction accuracy was high with GPS data sampling rates up to three minutes apart. The minor loss of accuracy linked to model classification is largely compensated by the savings in time required for analysis, especially in a context of nations or organizations with limited resources. This method could be applied to larger datasets at a national or international scale to identify and more adequately manage fishing effort.

Genetic diversity of clinical Salmonella enterica serovar Typhimurium in a university hospital of south Tunisia, 2000-2013.

Typhimurium is one of the main Salmonella serovar responsible for non-typhoidal gastro-enteritis in Tunisia. Here, we aimed to assess the genetic diversity of 88 clinical Salmonella Typhimurium strains recovered during 14 years from 2000 to 2013. Phage typing, CRISPR polymorphisms (CRISPOL), pulsed-field gel electrophoresis (PFGE), multi-locus variable-number tandem repeat analysis (MLVA) and Whole genome sequencing (WGS) were used to study the relatedness and spatio-temporal evolution of Salmonella Typhimurium populations (Typhimurium (n = 81), monophasic (n = 3) and nonmotile (n = 4) variants). Seven-locus MLST from whole genome assemblies showed that all isolates, except one, belonged to ST19. The isolates were divided into 10 definitive phage (DT) types, dominated by DT104-L (39.8%), DT41 (14.8%), DT116 (11.4%) and DT120 (5.7%). Fifty-seven MLVA patterns (DI, 0.978) were obtained compared to 11 different CRISPOL types and 15 PFGE types (DI,0.845). For cgMLST analysis, 20 profiles were found. A total of 3056 SNPs were identified from the whole genome of the 88 Salmonella Typhimurium isolates. These SNPs resolved these isolates into 86 SNP haplotypes. The phylogeny result allocated most Salmonella Typhimurium isolates into four distinct clades and seven subclades. Genetic diversity between the four clades ranged in the order of 249 to 720 nucleotide changes. The prevalent phage type DT104L formed a major clade on the phylogenetic tree. Pairwise SNP differences between the strains of this clade ranged between 0 and 59. SNP-based WGS typing seems to be the most valuable molecular markers for studying the evolutionary relationships of homogeneous serovar Typhimurium isolates.

A genoserotyping system for a fast and objective identification of Salmonella serotypes commonly isolated from poultry and pork food sectors in Belgium.

Humans are mostly contaminated by Salmonella through the consumption of pork- and poultry-derived food products. Therefore, a strict monitoring of Salmonella serotypes in food-producing animals is needed to limit the transmission of the pathogen to humans. Additionally, Salmonella can lead to economic loss in the food sector. Previously, a genoserotyping method using the MOL-PCR and Luminex technology was developed for the identification of the 6 Salmonella serotypes, and their variants, subjected to an official control in the Belgian food sector. In this study, 3 additional assays using the same technology were developed for the rapid and cost-effective detection of 13 dangerous highly invasive serotypes or other serotypes frequently isolated from the Belgian poultry and pork sector, i.e. Agona, Anatum, Brandenburg, Choleraesuis, Derby, Enteritidis vaccine strains, Gallinarum var. Gallinarum/Pullorum, Livingstone, Mbandaka, Minnesota, Ohio, Rissen and Senftenberg. Moreover, the previously developed first MOL-PCR assay was improved for S. Paratyphi B and serogroup O:3 detection. Finally, a Decision Support System hosted by a web application was created for an automatic and objective interpretation of the Luminex raw data. The 3 new assays and the modifications of the first assay were validated with a 100% accuracy, using 553 Salmonella and non-Salmonella strains in total.

One-Pot Suzuki-Hydrogenolysis Protocol for the Modular Synthesis of 2,5-Diaryltetrazoles.

2,5-Diaryltetrazoles are a diverse range of compounds of considerable interest within the field of photochemistry as a valuable precursor of the nitrile imine 1,3-dipole. Current literature approaches toward this heterocycle remain unsuitable for the practical synthesis of a library of these derivatives. Herein, we disclose the development of a modular approach toward 2,5-diaryltetrazoles compatible with an array-type protocol, facilitated by a tandem Suzuki-hydrogenolysis approach.

Transition-Metal-Free Coupling of 1,3-Dipoles and Boronic Acids as a Sustainable Approach to C-C Bond Formation.

The need for alternative, complementary approaches to enable C-C bond formation within organic chemistry is an on-going challenge in the area. Of particular relevance are transformations that proceed in the absence of transition-metal reagents. In the current study, we report a comprehensive investigation of the coupling of nitrile imines and aryl boronic acids as an approach towards sustainable C-C bond formation. In situ generation of the highly reactive 1,3-dipole facilitates a Petasis-Mannich-type coupling via a nucleophilic boronate complex. The introduction of hydrazonyl chlorides as a complementary nitrile imine source to the 2,5-tetrazoles previously reported by our laboratory further broadens the scope of the approach. Additionally, we exemplify for the first time the extension of this protocol into another 1,3-dipole, through the synthesis of aryl ketone oximes from aryl boronic acids and nitrile N-oxides.

Rhodacyclopentanones as Linchpins for the Atom Economical Assembly of Diverse Polyheterocycles.

We outline a conceptual blueprint that provides direct and atom economical access to a wide range of complex polyheterocycles. Our method capitalizes on the ambiphilic reactivity of rhodacyclopentanones that arise upon exposure of cyclopropanes to Rh(I) catalysts and CO. Using this approach, a wide array of polycyclizations are achieved, including variants that involve powerful dearomatizations and medium ring formations.

A multiplex oligonucleotide ligation-PCR method for the genoserotyping of common Salmonella using a liquid bead suspension assay.

Salmonella is a major pathogen having a public health and economic impact in both humans and animals. Six serotypes of the Salmonella genus are mentioned in the Belgian and European regulation as to be rapidly excluded from the food chain (EU regulation N°2160/2003, Belgian royal decree 27/04/2017). The reference method for Salmonella serotyping, including slide-agglutination and biochemical tests, is time-consuming, expensive, not always objective, and therefore does not match the fast identification criteria required by the legislation. In this study, a molecular method, using genetic markers detected by Multiplex Oligonucleotide Ligation - PCR and Luminex technology, was developed for the identification of the 6 Salmonella serotypes and their variants subjected to an official control. The resulting method was validated with the analysis of 971 Salmonella isolated from different matrixes (human, animal, food or environment) and 33 non-Salmonella strains. The results were compared with the reference identifications, achieving an accuracy of 99.7%. The cost-effective high-throughput genoserotyping assay is performed in 1 day and generates objective results, thanks to the automatic interpretation of raw data using a barcode system. In conclusion, it is fully adapted to the implementation in first line laboratories and meets the requirements of the regulation.

Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target.

Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.

The Ethylene Precursor ACC Affects Early Vegetative Development Independently of Ethylene Signaling.

The plant hormone ethylene plays a pivotal role in virtually every aspect of plant development, including vegetative growth, fruit ripening, senescence, and abscission. Moreover, it acts as a primary defense signal during plant stress. Being a volatile, its immediate biosynthetic precursor, 1-aminocyclopropane-1-carboxylic acid, ACC, is generally employed as a tool to provoke ethylene responses. However, several reports propose a role for ACC in parallel or independently of ethylene signaling. In this study, pharmacological experiments with ethylene biosynthesis and signaling inhibitors, 2-aminoisobutyric acid and 1-methylcyclopropene, as well as mutant analyses demonstrate ACC-specific but ethylene-independent growth responses in both dark- and light-grown Arabidopsis seedlings. Detection of ethylene emanation in ethylene-deficient seedlings by means of laser-based photoacoustic spectroscopy further supports a signaling role for ACC. In view of these results, future studies employing ACC as a proxy for ethylene should consider ethylene-independent effects as well. The use of multiple knockout lines of ethylene biosynthesis genes will aid in the elucidation of the physiological roles of ACC as a signaling molecule in addition to its function as an ethylene precursor.