Sponges are critical components of marine reefs due to their high filtering capacity, wide abundance, and alteration of biogeochemical cycling. Here, we characterized dissolved organic matter (DOM) ...composition in the sponge holobiont exhalent seawater of a loggerhead sponge (Spheciospongia vesparium) and in ambient seawater in Florida Bay (USA), as well as the microbial responses to each DOM pool through dark incubations. The sponge holobiont removed 6% of the seawater dissolved organic carbon (DOC), utilizing compounds that were low in carbon and oxygen, yet high in nitrogen content relative to the ambient seawater. The microbial community accessed 7% of DOC from the ambient seawater during a 5-day incubation but only 1% of DOC from the sponge exhalent seawater, suggesting a decrease in lability possibly due to holobiont removal of nitrogen-rich compounds. If this holds true for other sponges, it may have important implications for DOM lability and cycling in coastal environments.
•S. vesparium holobiont altered the DOM composition of seawater in Florida Bay.•Sponge-microbial holobiont uptook ~6% of DOC from ambient seawater.•Compounds with low carbon, low oxygen, and high nitrogen content were depleted.•Sponge exhalent water was enriched in large, more aromatic compounds.•Microbial consumption of DOC was higher in seawater than in sponge exhalent water.
Dissolved organic matter (DOM) is a large and complex mixture of compounds with source inputs that differ with location, season, and environmental conditions. Here, we investigated drivers of DOM ...composition changes in a marsh‐dominated estuary off the southeastern United States. Monthly water samples were collected at a riverine and estuarine site from September 2015 to September 2016, and bulk, optical, and molecular analyses were conducted on samples before and after dark incubations. Results showed that river discharge was the primary driver changing the DOM composition at the mouth of the Altamaha River. For discharge higher than ~150 m3/s, dissolved organic carbon (DOC) concentrations and the terrigenous character of the DOM increased approximately linearly with river flow. For low discharge conditions, a clear signature of salt marsh‐derived compounds was observed in the river. At the head of Sapelo Sound, changes in DOM composition were primarily driven by river discharge and possibly by summer algae blooms. Microbial consumption of DOC was larger during periods of high discharge at both sites, potentially due to the higher mobilization and influx of fresh material to the system. The Georgia coast was hit by Hurricane Matthew in October 2016, which resulted in a large input of carbon to the estuary. The DOC concentration was ~2 times higher and DOM composition was more aromatic with a stronger terrigenous signature compared to the seasonal maximum observed earlier in the year during peak river discharge conditions. This suggests that extreme events notably impact DOM quantity and quality in estuarine regions.
Plain Language Summary
Dissolved organic matter (DOM) is a crucial component of aquatic ecosystems and characterizing how its composition and concentration change is important to better understand the carbon cycle. Composition and quantity of DOM can vary spatially and temporally due to a variety of factors, including biological activity, precipitation patterns, and proximity to source inputs such as rivers, salt marshes, and the open ocean. To track these changes, monthly water samples were collected and analyzed over the course of a year in a marsh‐dominated estuary off the Georgia coast, USA. River flow was shown to be an important factor controlling the amount and type of DOM present at both riverine (Altamaha River) and estuarine (Sapelo Sound) locations. In months with high river flow, organic matter contents were higher and had more terrestrially derived compounds compared to months with low river flow. Additionally, Hurricane Matthew was shown to significantly alter the organic matter at Sapelo Sound, suggesting that extreme events greatly impact DOM quantity and quality in estuarine regions.
Key Points
Changes in DOM composition over a year at the Altamaha River and Sapelo Sound are strongly correlated with river discharge
High river discharge conditions are characterized by DOM with stronger terrigenous signature and higher microbial utilization rates
Passage of Hurricane Matthew resulted in large input of terrigenous DOM to Sapelo Sound, greatly increasing DOC concentrations
infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality, and associated health care costs. The major risk factor for CDI is antimicrobial ...therapy, which disrupts the normal gut microbiota and allows
to flourish. Treatment of CDI with antimicrobials is generally effective in the short term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective nonantimicrobial therapy. Here, we report a highly potent small-molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intrarectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated efficacy similar to that of vancomycin in a hamster disease model. Overall, these results demonstrate that small-molecule inhibition of
toxin UDP-glucose hydrolysis activity is a promising nonantimicrobial approach to the treatment of CDI.
Rivers play an important role in the transport of organic carbon from terrestrial to marine environments. A significant portion of this material is black carbon (BC), a residue of incomplete biomass ...and fossil fuel combustion. BC is mobilized in fluvial systems as both particulate BC (PBC) and dissolved BC (DBC), and the export of BC to coastal environments may have significant implications for carbon cycling in marine environments. However, while little is known regarding the potential connectivity between riverine export of PBC and DBC or the potential importance of such a relationship in constraining future BC budgets, current knowledge suggests that fluvial export of PBC and DBC are decoupled in small fire‐impacted watersheds. This study aims to further address this subject on a larger watershed scale. For this study, 13 monthly samples were collected (September 2015 to September 2016) near the mouth of the Altamaha River, Georgia. PBC and DBC were characterized using the benzenze polycarboxylic acid method. Seasonal hydrology and regional shifts in storm events play an important role for both PBC and DBC export during high flow months. The DBC concentrations were comparable among wet and dry seasons, whereas evidence of seasonal salt water intrusions suggests an additional estuarine contribution of PBC at the sampling location. The DBC and PBC fluxes were generally coupled, although this pattern was disrupted during initial storm pulses. While this is the first report of potential coupling between DBC and PBC export, environmental drivers controlling this behavior between DBC and PBC remain to be constrained.
Plain Language Summary
Rivers play a critical role in the annual transport of organic material from terrestrial to marine environments. A significant portion of this material is a residue formed from incomplete combustion of plants and fossil fuels. Such pyrogenic materials can be mobilized from soils to rivers and transported in both particulate and dissolved forms. Their export to coastal environments may have significant implications for carbon cycling in marine environments. Here we study a subtropical watershed covering most of the U.S. state of Georgia, to investigate the effect of climate—particularly precipitation—on the export and linkages between particulate and dissolved combustion products.
Key Points
Hydrological controls on BC mobilization may be more complex than previously suggested
Seasonal dynamics suggests that PBC and DBC may be coupled during baseflow conditions but not during high flow
PBC export was also linked to seasonal hydrology, but sources appeared to be highly variable throughout the sampling period
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•Highly potent C. diff. toxin B (TcdB) inhibitors identified.•Improved plasma stability enabled compound progression into in vivo models of CDI.•Compound 11d efficacious in hamster ...survival model of CDI upon oral dosing.
Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.
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The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A ...high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1–5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization.
The interconnected estuarine complex of the Altamaha River and adjacent sounds located in Georgia (USA) functions as a hotspot for organic matter transformation as it is transported to the Atlantic ...Ocean. Here, we investigated how dissolved organic matter (DOM) composition changes both spatially and seasonally along the estuary and how it influences bacterial processing. Surface samples were collected during high tide at fifteen stations throughout the estuary in April, July, October 2017, and January 2018. Bulk, optical, and molecular analyses were conducted on samples before and after dark incubations to assess DOM sources and transformation patterns in the system. The dominant driver of change in DOM composition was found to be the terrigenous‐marine gradient in organic matter sources. Six distinct clusters were identified based on the terrigenous signature of the DOM pool, explaining 45% of the variance in DOM composition in the system. Bacterial consumption of dissolved organic carbon (DOC) was strongly influenced by DOM composition, with increased degradation rates for DOM with a larger terrigenous character. However, changes in optical properties suggested that less aromatic DOM that co‐varied with the terrigenous material was preferentially degraded. The passage of Hurricane Irma in September 2017 resulted in a 27% ± 7% increase in DOC content, likely due to inundation associated with storm surge and increased local precipitation, and DOC biodegradation was 17% ± 8% higher than during summer. These effects lasted for at least one month after the storm, revealing that hurricanes can have a large impact on DOM composition and cycling in coastal systems.
IL-10 has been previously called cytokine synthesis inhibiting factor, produced mostly by Th2 cells, macrophages and CD8+ cell clones. IL-10 is capable of inhibiting the synthesis of several ...cytokines from different cells, antigen or mitogen activated. IL-10 exerts its inhibition at the mRNA transcriptional and translational level. In addition, IL-10 is a co-stimulatory cytokine on activated T cells. For example, IL-10 inhibits NK cell activity, the production of Th1 cytokines, cytokines generated by peripheral blood mononuclear cells, and macrophage activity. On the other hand, IL-10 exerts immunostimulatory effects on B cells, cytotoxic T cell development and thymocytes. In mast cells derived from CD4+/CD133+ cells, IL-10 inhibits IL-6 and TNFα, and prostaglandin E
1 and E
2 induced by IL-6. Here, we report for the first time that IL-10 fails to inhibit tryptase and IL-6 from human mast cell-1 (HMC-1) and human umbilical cord blood-derived mast cells.
Synthesis and structure–activity relationships (SAR) of a novel series of vasopressin V₁b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been ...identified with low nanomolar affinity for the V₁b receptor and good selectivity with respect to related receptors V₁ₐ, V₂ and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an ...extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.
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