Sediment grain size and benthic community structure in the eastern English Channel: Species-dependent responses and environmental influence.

This study addresses the scarcity of evidence on the relationship between benthic communities and coarse-grained sediments in the eastern English Channel. The region's geological history contributes to its predominantly coarse sediment composition. The study employs ternary plots to visualize benthic species' preferences and tolerance for sediment types, revealing their effectiveness. Redundancy Analyses (RDA) and species-level quantile regressions explore the influence of grain size on benthic species distribution. The results indicate a moderate impact of grain size, influenced by hydrodynamics. Estuaries, particularly the Seine Estuary, significantly shape benthic species distribution. Quantile regressions underscore the varied responses of benthic communities along the grain size gradient. The study underscores the importance of considering coarse sediments, offering insights into the complex relationship between benthic communities and sediment characteristics.

Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.

Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound 28), a potent and selective pan-SIK inhibitor (IC50: 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for SIK3). Characterization of the first human SIK3 crystal structure provided an understanding of the binding mode and kinome selectivity of the chemical series. GLPG3312 demonstrated both anti-inflammatory and immunoregulatory activities in vitro in human primary myeloid cells and in vivo in mouse models.

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure-activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

Sediment migrations drive the dynamic of macrobenthic ecosystems in subtidal sandy bedforms.

A traditional taxonomic approach coupled to a biological traits analysis was conducted in order to provide a new insight into macrobenthic communities associated with subtidal sandy environments. Results suggest that the macro-scale distribution of benthic communities is mainly driven by the migration rate of bedforms (sandbank, barchan dune and transversal dune) which changes the sediment grain size and reduces macrobenthic diversity. A classic scheme of species/traits succession was also observed from less to more physically disturbed areas. Finally, the high frequency of migration events homogenized macrobenthic communities between the troughs to the crest of bedforms. As bedforms areas are targeted for the commissioning of offshore windfarms the information provided by the present paper will be particularly useful to implement the environmental impact assessment required for such activities at sea.

Linking multiple facets of biodiversity and ecosystem functions in a coastal reef habitat.

Reef-building species play key roles in promoting local species richness and regulating ecosystem functions like biogeochemical fluxes. We evaluated the functioning of a habitat engineered by the reef-building polychaete Sabellaria alveolata, by measuring oxygen and nutrient fluxes in the reef structures and in the soft-sediments nearby. Then, we investigated the relative importance of temperature, the engineer S. alveolata, and different facets of macrofauna diversity (taxonomic, functional diversity and identity), on the reef biogeochemical fluxes using multiple linear regressions and effect sizes. The reef fluxes were more intense than the soft-sediment fluxes and mainly driven by the engineer biomass and abundance, stressing the importance of these biogenic structures. Higher water temperatures and an intermediate level of associated macrofauna functional dispersion weighted only by abundance (i.e. intermediate biological trait variability) maximized the reef's global biogeochemical functioning. Ultimately, the physical degradation of the reefs could lead to lower levels of functioning.

Renewable energy homes for marine life: Habitat potential of a tidal energy project for benthic megafauna.

An increasing number of offshore structures are being deployed worldwide to meet the growing demand for renewable energy. Besides energy production, these structures can also provide new artificial habitats to a diversity of fish and crustacean species. This study characterises how concrete mattresses that stabilise the submarine power cable of a tidal energy test site can increase habitat capacity for benthic megafauna. A five-year monitoring, which relied on both visual counts and video-based surveys by divers, revealed that these mattresses provide a suitable habitat for 5 taxa of large crustaceans and fish. In particular, two commercially valuable species, i.e. the edible crab Cancer pagurus and the European lobster Homarus gammarus, showed a constant occupancy of these artificial habitats throughout the course of the project. The shape and the number of shelters available below individual mattresses largely determine potential for colonisation by mobile megafauna. Local physical characteristics of the implantation site (e.g. substratum type, topography, exposition to current etc.) significantly impact amount and type of shelters provided by the concrete mattresses. Thus, to characterise habitat potential of artificial structures, it is not only essential to consider (i) the design of the structures, but also to (ii) account for their interactions with local environmental conditions when deployed on the seafloor.

Long-term spatio-temporal changes of the muddy fine sand benthic community of the Bay of Seine (eastern English Channel).

In the English Channel, the eastern Bay of Seine is exposed to numerous anthropogenic disturbances, in particular major changes in sediment dynamics, which are expected to greatly impact benthic communities. To assess the long-term effects of these stressors on the muddy fine sand benthic community, an original long-term monitoring program has been implemented since 1988. It is based on the sampling of a network of 60 stations during seven surveys over 28 years from 1988 to 2016. We investigate changes of species density, species composition and species diversity at different scales (α-diversity, ß-diversity and γ-diversity). Contrary to results obtained in many coastal areas, our results showed a long-term persistence of the community in terms of species composition and structure although a general shift towards muddy sediment has resulted in increased colonisation by species associated with muddy habitats and a decrease in spatial beta diversity.

Impact of magnetic fields generated by AC/DC submarine power cables on the behavior of juvenile European lobster (Homarus gammarus).

The number of submarine power cables using either direct or alternating current is expected to increase drastically in coming decades. Data concerning the impact of magnetic fields generated by these cables on marine invertebrates are scarce. In this context, the aim of this study was to explore the potential impact of anthropogenic static and time-varying magnetic fields on the behavior of recently settled juvenile European lobsters (Homarus gammarus) using two different behavioral assays. Day-light conditions were used to stimulate the sheltering behavior and facilitate the video tracking. We showed that juvenile lobsters did not exhibit any change of behavior when submitted to an artificial magnetic field gradient (maximum intensity of 200 µT) compared to non-exposed lobsters in the ambient magnetic field. Additionally, no influence was noted on either the lobsters' ability to find shelter or modified their exploratory behavior after one week of exposure to anthropogenic magnetic fields (225 ±â€¯5 µT) which remained similar to those observed in control individuals. It appears that static and time-varying anthropogenic magnetic fields, at these intensities, do not significantly impact the behavior of juvenile European lobsters in daylight conditions. Nevertheless, to form a complete picture for this biological model, further studies are needed on the other life stages as they may respond differently.

Towards Gram-negative antivirulence drugs: new inhibitors of HldE kinase.

Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relationship of this series of inhibitors led to highly potent compounds.

Impact of the Phaeocystis globosa spring bloom on the intertidal benthic compartment in the eastern English Channel: a synthesis.

From 1999 to 2005, studies carried out in the frame of regional and national French programs aimed to determine whether the Phaeocystis globosa bloom affected the intertidal benthic communities of the French coast of the eastern English Channel in terms of composition and/or functioning. Study sites were chosen to cover most of the typical shore types encountered on this coast (a rocky shore, an exposed sandy beach and a small estuary). Both the presence of active Phaeocystis cells and their degradation product (foam) did have a significant impact on the studied shores. The primary production and growth rates of the kelp Saccharina latissima decreased during the bloom because of a shortage of light and nutrient for the macroalgae. On sandy sediments, the benthic metabolism (community respiration and community primary production), as well as the nitrification rate, were enhanced during foam deposits, in relation with the presence of bacteria and active pelagic cells within the decaying colonies. In estuarine sediments, the most impressive impact was the formation of a crust at the sediment surface due to drying foam. This led to anoxic conditions in the surface sediment and resulted in a high mortality among the benthic community. Some organisms also tended to migrate upward and were then directly accessible to the higher trophic level represented by birds. Phaeocystis then created a shortcut in the estuarine trophic network. Most of these modifications lasted shortly and all the systems considered came back to their regular properties and activities a few weeks after the end of the bloom, except for the most impacted estuarine area.

Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators.

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

Consequences of spring phytodetritus sedimentation on the benthic compartment along a depth gradient in the Eastern English Channel.

Phaeocystis blooms are of major importance in the Eastern English Channel, where they significantly contribute to spring organic matter input with chlorophyll concentrations commonly higher than 30 microgl(-1) in the water column. Post-bloom deposition of Phaeocystis derived mucilaginous compounds has been shown to have a major importance on benthic intertidal systems, but resulting mineralization processes and consequences on the macrobenthic compartment remain poorly documented in subtidal areas. In this frame, a study was performed along the French coast of the English Channel to quantify mineralization processes, as well as potential consequences on subtidal sediments, especially their geochemistry and associated macrofaunal communities. Seven stations were studied along a depth gradient during four cruises: before (March), during (April, May) and after (June) the spring bloom. Sediment characteristics and organic carbon content were described, as well as sediment-water fluxes of oxygen and ammonium. Macrofaunal characteristics were also analyzed. Stations were chosen as representative of the various benthic communities present in the area, which are directly linked to the granulometric characteristics of the sediments. To account for the general functioning of the water column, characterized by a coastal flow where higher concentrations of Phaeocystis are generally recorded, similar communities were sampled inshore and offshore, when possible: (i) the Abra alba community located only close to the coast, (ii) the Ophelia borealis community located inshore and offshore, and (iii) the Amphioxus lanceolatus community located inshore and offshore. Generally, low exchange rates of oxygen and ammonium were measured (respectively, in the range 50-150 micromol O2 m(-2)h(-1) and -25 to 35 micromol NH4+ m(-2)h(-1)) between the water column and the muddy-sand to coarse sand permeable sediments, as a consequence of the low organic carbon content due to the high hydrodynamic forcing. As a consequence of organic matter accumulation in surficial sediments probably resulting from Phaeocystis post-bloom deposition, an increase of sediment oxygen demand and ammonium release was clearly evidenced up to 660 micromol O2 m(-2)h(-1) and 205 micromol NH4+ m(-2)h(-1) in May, only in stations located close to the coast (<8 kms), in the A. alba community. Despite those significant biogeochemical changes in surficial sediments, no significant consequence was pointed out on macrofauna, neither in the O. borealis and A. lanceolatus communities, nor in the coastal A. alba community. Most of the temporal variations recorded might be attributed to the common spring population dynamics, but this study highlights the potential use of geochemical parameters as a forewarning signal of benthic disequilibrium.

Does the Phaeocystis bloom affect the diel migration of the suprabenthos community?

The suprabenthos comprises all bottom-dependent animals, mainly crustaceans (including decapods and peracarids), which perform--with varying amplitude, intensity and regularity--seasonal or daily vertical migrations above the sea floor. The presence of organisms in the Benthic Boundary Layer is determined by two general factors: (1) organism behaviour, which depends on the light penetration in the water column and (2) boundary-layer hydrodynamics. In the coastal zone of the eastern English Channel, during the spring Phaeocystis bloom, the presence of gelatinous colonies modifies the penetration of light in the water column, which may seriously affect the abundance and/or the behaviour of the suprabenthos community. To clarify this point, 19 suprabenthic hauls were taken with a modified Macer-GIROQ sledge both during the day and during the night, from March to June 2002 (i.e., before, during and after the bloom). Two sites, located in the coastal and offshore areas of the Ophelia medium sand macrobenthic community were investigated. The bloom had no effect on species richness and abundance in either site. However, the diel migrations of some dominant species--such as the cumaceans Pseudocuma longicornis and Pseudocuma similis, the mysid Gastrosaccus spinifer and the amphipod Stenothoe marina--were modified. During the bloom, diurnal and nocturnal suprabenthic abundances were similar, and in the absence of bloom, species remained benthic during the day. The permanent presence of suprabenthic species in the Benthic Boundary Layer could have a consequence on their predation by fish (mainly juveniles which preferentially consume small crustaceans in their diet), unless fish behaviour and predation efficiency--especially for visual predators--are also disturbed by changes in light intensity.

Individual-based simulation of the spatial and temporal dynamics of macroinvertebrate functional groups provides insights into benthic community assembly mechanisms.

The complexity and scales of the processes that shape communities of marine benthic macroinvertebrates has limited our understanding of their assembly mechanisms and the potential to make projections of their spatial and temporal dynamics. Individual-based models can shed light on community assembly mechanisms, by allowing observed spatiotemporal patterns to emerge from first principles about the modeled organisms. Previous work in the Rance estuary (Brittany, France) revealed the principal functional components of its benthic macroinvertebrate communities and derived a set of functional relationships between them. These elements were combined here for the development of a dynamic and spatially explicit model that operates at two spatial scales. At the fine scale, modeling each individual's life cycle allowed the representation of recruitment, inter- and intra-group competition, biogenic habitat modification and predation mortality. Larval dispersal and environmental filtering due to the tidal characteristics of the Rance estuary were represented at the coarse scale. The two scales were dynamically linked and the model was parameterized on the basis of theoretical expectations and expert knowledge. The model was able to reproduce some patterns of α- and ß-diversity that were observed in the Rance estuary in 1995. Model analysis demonstrated the role of local and regional processes, particularly early post-settlement mortality and spatially restricted dispersal, in shaping marine benthos. It also indicated biogenic habitat modification as a promising area for future research. The combination of this mechanism with different substrate types, along with the representation of physical disturbances and more trophic categories, could increase the model's realism. The precise parameterization and validation of the model is expected to extend its scope from the exploration of community assembly mechanisms to the formulation of predictions about the responses of community structure and functioning to environmental change.

Latitudinal Patterns in European Seagrass Carbon Reserves: Influence of Seasonal Fluctuations versus Short-Term Stress and Disturbance Events.

Seagrass meadows form highly productive and valuable ecosystems in the marine environment. Throughout the year, seagrass meadows are exposed to abiotic and biotic variations linked to (i) seasonal fluctuations, (ii) short-term stress events such as, e.g., local nutrient enrichment, and (iii) small-scale disturbances such as, e.g., biomass removal by grazing. We hypothesized that short-term stress events and small-scale disturbances may affect seagrass chance for survival in temperate latitudes. To test this hypothesis we focused on seagrass carbon reserves in the form of starch stored seasonally in rhizomes, as these have been defined as a good indicator for winter survival. Twelve Zostera noltei meadows were monitored along a latitudinal gradient in Western Europe to firstly assess the seasonal change of their rhizomal starch content. Secondly, we tested the effects of nutrient enrichment and/or biomass removal on the corresponding starch content by using a short-term manipulative field experiment at a single latitude in the Netherlands. At the end of the growing season, we observed a weak but significant linear increase of starch content along the latitudinal gradient from south to north. This agrees with the contention that such reserves are essential for regrowth after winter, which is more severe in the north. In addition, we also observed a weak but significant positive relationship between starch content at the beginning of the growing season and past winter temperatures. This implies a lower regrowth potential after severe winters, due to diminished starch content at the beginning of the growing season. Short-term stress and disturbances may intensify these patterns, because our manipulative experiments show that when nutrient enrichment and biomass loss co-occurred at the end of the growing season, Z. noltei starch content declined. In temperate zones, the capacity of seagrasses to accumulate carbon reserves is expected to determine carbon-based regrowth after winter. Therefore, processes affecting those reserves might affect seagrass resilience. With increasing human pressure on coastal systems, short- and small-scale stress events are expected to become more frequent, threatening the resilience of seagrass ecosystems, particularly at higher latitudes, where populations tend to have an annual cycle highly dependent on their storage capacity.

The ecological quality status of the Bay of Seine and the Seine estuary: use of biotic indices.

Using recent indices developed, in part, for use under the European Water Framework Directive (AMBI, BENTIX, BOPA, BQI, I2EC and the trophic index ITI), the ecological quality status of two highly contaminated environments--the Bay of Seine and the Seine estuary (Eastern English Channel)--was determined on several spatial and temporal scales. Data from 604 observations gathered over a 14-year period (1988-2002) were analyzed, and the results used to show the relationship between biotic indices, environmental variables and classic descriptors (e.g., number of species, total abundance, dominance index, ES(50) and Shannon/Brillouin diversities). Though the specific ecological quality (EcoQ) values calculated with the various indices were different, the overall trend of the results was similar. Synthesizing the values produced by the six indices used in the study allowed attribution of a high to good EcoQ status to the Bay of Seine and a moderate EcoQ to the estuary. The mesh size used when processing samples was proved to have no effect in winter on the EcoQ values for either body of water.

Process-driven and biological characterisation and mapping of seabed habitats sensitive to trawling.

The increase of anthropogenic pressures on the marine environment together with the necessity of a sustainable management of marine living resources have underlined the need to map and model coastal environments, particularly for the purposes of spatial planning and for the implementation of integrated ecosystem-based management approach. The present study compares outputs of a process-driven benthic habitat sensitivity (PDS) model to the structure, composition and distribution of benthic invertebrates in the Eastern English Channel and southern part of the North Sea. Trawl disturbance indicators (TDI) computed from species biological traits and benthic community composition were produced from samples collected with a bottom trawl. The TDI was found to be highly correlated to the PDS further validating the latter's purpose to identify natural process-driven pattern of sensitivity. PDS was found to reflect an environmental potential that may no longer be fully observable in the field and difference with in situ biological observations could be partially explained by the spatial distribution of fishery pressure on the seafloor. The management implication of these findings are discussed and we suggest that, used in conjunction with TDI approaches, PDS may help monitor management effort by evaluating the difference between the current state and the presumed optimal environmental status of marine benthic habitats.

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.

Novel HldE-K inhibitors leading to attenuated Gram negative bacterial virulence.

We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 µg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.