Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFκB paradigm

<p>Abstract</p> <p>Background</p> <p>Ectodysplasin-A appears to be a critical component of branching morphogenesis. Mutations in mouse <it>Eda </it>or human <it>EDA </it>are associated with absent or hypoplastic sweat glands, sebaceous glands, lacrimal glands, salivary glands (SMGs), mammary glands and/or nipples, and mucous glands of the bronchial, esophageal and colonic mucosa. In this study, we utilized <it>Eda</it>^{<it>Ta </it>}(Tabby) mutant mice to investigate how a marked reduction in functional Eda propagates with time through a defined genetic subcircuit and to test the proposition that canonical NFκB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of <it>Eda </it>polymorphism.</p> <p>Results</p> <p>The quantitative systems analyses do not support the stated hypothesis. For most NFκB-regulated genes, the observed time course of gene expression is nearly unchanged in Tabby (<it>Eda</it>^<it>Ta</it>) as compared to wildtype mice, as is NFκB itself. Importantly, a subset of genes is dramatically differentially expressed in Tabby (<it>Edar</it>, <it>Fgf8</it>, <it>Shh</it>, <it>Egf</it>, <it>Tgfa</it>, <it>Egfr</it>), strongly suggesting the existence of an alternative Eda-mediated transcriptional pathway pivotal for SMG ontogeny. Experimental and <it>in silico </it>investigations have identified C/EBPα as a promising candidate.</p> <p>Conclusion</p> <p>In Tabby SMGs, upregulation of the Egf/Tgfα/Egfr pathway appears to mitigate the potentially severe abnormal phenotype predicted by the downregulation of Fgf8 and Shh. Others have suggested that the buffering of the phenotypic outcome that is coincident with variant Eda signaling could be a common mechanism that permits viable and diverse phenotypes, normal and abnormal. Our results support this proposition. Further, if branching epithelia use variations of a canonical developmental program, our results are likely applicable to understanding the phenotypes of other branching organs affected by <it>Eda </it>(<it>EDA</it>) mutation.</p

Sediment remediation using activated carbon: amending knowledge gaps

Many coastal sediments have accumulated large quantities of contaminants from past anthropogenic activities and now act as a secondary emission source of legacy pollutants to coastal ecosystems. New sediment remediation strategies are needed to address widespread sediment pollution. This thesis focuses on the harbour of Oskarshamn in the Baltic Sea, contaminated by PAHs, PCBs, TBTs, dioxins, and metals from past emissions, and aims to improve knowledge on in situ sediment remediation using activated carbon, a strong sorbent for hydrophobic organic contaminants. Thin-layer capping using activated carbon aims to sequester contaminants in sediment and reduce their bioavailability to aquatic organisms without having to remove or physically isolate the contaminated sediment from the aquatic environment. Questions remain on the efficacy and persistence of activated carbon thin-layer capping in turbulent waters, and on potential adverse effects of activated carbon on benthic communities. We studied the role of activated carbon particle size on contaminant sequestration, sorbent retention (Paper I), and adverse effects in benthic macroinvertebrates (Paper III). We also assessed effects of activated carbon amendment on nutrient cycling and meiofauna communities (Paper II), and whether granular activated carbon (GAC, &gt;300 µm) reduces toxicity to the benthic sentinel amphipod Monoporeia affinis in Oskarshamn harbour (Paper IV). We found that powdered activated carbon (PAC, &lt;300 µm) is much more effective in sequestering PAHs and PCBs than GAC in the short term (Paper I), but that PAC is readily resuspended in turbulent water, whereas GAC may remain on the sediment surface, leading to a higher persistence of GAC over time (Paper I). Thin-layer capping with PAC raised porewater pH and reduced meiofauna abundance, nitrate reduction, nitrate release fluxes, and phosphate release fluxes by at least 50 % (Paper II). This indicates that thin-layer capping with PAC affected both sediment microbial and meiofaunal communities, potentially through the increased pH and sequestration of dissolved organic matter onto activated carbon, rendering it less available to microbial organisms. We observed strong biological responses in macroinvertebrates, with reduced weight, carbon assimilation, and gut microvilli in the polychaete Marenzelleria spp. exposed to ingestible PAC, contrasted by increased weight and carbon assimilation in polychaetes exposed to noningestible GAC (Paper III). This indicates that amendment with PAC caused starvation, i.e., that the polychaete ceased ingesting sediment or that PAC reduced the bioaccessibility of food co-ingested with the sorbent. These effects were present but less pronounced in the clam Limecola balthica (Paper III), indicating that biological responses are species dependent. A toxicity bioassay (Paper IV) showed that sediment amendment using GAC effectively reduced mortality and reproduction impairments in the amphipod Monoporeia affinis. Overall, the thesis demonstrates that GAC may have positive effects on benthic macroinvertebrates, high persistence in turbulent water, and reduces toxicity of highly contaminated sediments. We show that PAC is a highly effective sorbent, but may cause strong adverse effects on benthic macroinvertebrates, meiofauna, and microbial nutrient cycling. Thus, non-ingestible granular activated carbon appears to be a better choice for remediation of contaminated coastal sediments

Sediment remediation using activated carbon: amending knowledge gaps

Many coastal sediments have accumulated large quantities of contaminants from past anthropogenic activities and now act as a secondary emission source of legacy pollutants to coastal ecosystems. New sediment remediation strategies are needed to address widespread sediment pollution. This thesis focuses on the harbour of Oskarshamn in the Baltic Sea, contaminated by PAHs, PCBs, TBTs, dioxins, and metals from past emissions, and aims to improve knowledge on in situ sediment remediation using activated carbon, a strong sorbent for hydrophobic organic contaminants. Thin-layer capping using activated carbon aims to sequester contaminants in sediment and reduce their bioavailability to aquatic organisms without having to remove or physically isolate the contaminated sediment from the aquatic environment. Questions remain on the efficacy and persistence of activated carbon thin-layer capping in turbulent waters, and on potential adverse effects of activated carbon on benthic communities. We studied the role of activated carbon particle size on contaminant sequestration, sorbent retention (Paper I), and adverse effects in benthic macroinvertebrates (Paper III). We also assessed effects of activated carbon amendment on nutrient cycling and meiofauna communities (Paper II), and whether granular activated carbon (GAC, &gt;300 µm) reduces toxicity to the benthic sentinel amphipod Monoporeia affinis in Oskarshamn harbour (Paper IV). We found that powdered activated carbon (PAC, &lt;300 µm) is much more effective in sequestering PAHs and PCBs than GAC in the short term (Paper I), but that PAC is readily resuspended in turbulent water, whereas GAC may remain on the sediment surface, leading to a higher persistence of GAC over time (Paper I). Thin-layer capping with PAC raised porewater pH and reduced meiofauna abundance, nitrate reduction, nitrate release fluxes, and phosphate release fluxes by at least 50 % (Paper II). This indicates that thin-layer capping with PAC affected both sediment microbial and meiofaunal communities, potentially through the increased pH and sequestration of dissolved organic matter onto activated carbon, rendering it less available to microbial organisms. We observed strong biological responses in macroinvertebrates, with reduced weight, carbon assimilation, and gut microvilli in the polychaete Marenzelleria spp. exposed to ingestible PAC, contrasted by increased weight and carbon assimilation in polychaetes exposed to noningestible GAC (Paper III). This indicates that amendment with PAC caused starvation, i.e., that the polychaete ceased ingesting sediment or that PAC reduced the bioaccessibility of food co-ingested with the sorbent. These effects were present but less pronounced in the clam Limecola balthica (Paper III), indicating that biological responses are species dependent. A toxicity bioassay (Paper IV) showed that sediment amendment using GAC effectively reduced mortality and reproduction impairments in the amphipod Monoporeia affinis. Overall, the thesis demonstrates that GAC may have positive effects on benthic macroinvertebrates, high persistence in turbulent water, and reduces toxicity of highly contaminated sediments. We show that PAC is a highly effective sorbent, but may cause strong adverse effects on benthic macroinvertebrates, meiofauna, and microbial nutrient cycling. Thus, non-ingestible granular activated carbon appears to be a better choice for remediation of contaminated coastal sediments

Capping with activated carbon reduces nutrient fluxes, denitrification and meiofauna in contaminated sediments

Sediment capping with activated carbon (AC) is an effective technique used in remediation of contaminated sediments, but the ecological effects on benthic microbial activity and meiofauna communities have been largely neglected. This study presents results from a 4-week experiment investigating the influence of two powdered AC materials (bituminous coal-based and coconut shell-derived) and one control material (clay) on biogeochemical processes and meiofauna in contaminated sediments. Capping with AC induced a 62‒63% decrease in denitrification and a 66‒87 % decrease in dissimilatory nitrate reduction to ammonium (DNRA). Sediment porewater pH increased from 7.1 to 9.0 and 9.7 after addition of bituminous AC and biomass-derived AC, respectively. High pH (&gt;8) persisted for at least two weeks in the bituminous AC and for at least 24 days in the coconut based AC, while capping with clay had no effect on pH. We observed a strong impact (nitrate fluxes being halved in presence of AC) on nitrification activity as nitrifiers are sensitive to high pH. This partly explains the significant decrease in nitrate reduction rates since denitrification was almost entirely coupled to nitrification. Total benthic metabolism estimated by sediment oxygen uptake was reduced by 30 and 43 % in presence of bituminous coal-based AC and coconut shell-derived AC, respectively. Meiofauna abundances decreased by 60‒62 % in the AC treatments. Taken together, these observations suggest that AC amendments deplete natural organic carbon, intended as food, to heterotrophic benthic communities. Phosphate efflux was 91 % lower in presence of bituminous AC compared to untreated sediment probably due to its content of aluminum (Al) oxides, which have high affinity for phosphate. This study demonstrates that capping with powdered AC produces significant effects on benthic biogeochemical fluxes, microbial processes and meiofauna abundances, which are likely due to an increase in porewater pH and to the sequestration of natural, sedimentary organic matter by AC particles

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants