Early Cretaceous biogeographic and oceanographic synthesis of Leg 123 (off Northwestern Australia)

Biogeographic observations made by Leg 123 shipboard paleontologists for Lower Cretaceous nannofossils, foraminifers, radiolarians, belemnites, and inoceramids are combined in this chapter to evaluate the paleoceanographic history of the northwestern Australian margin and adjacent basins. Each fossil group is characterized at specific intervals of Cretaceous time and compared with data from Tethyan and Southern Hemisphere high-latitude localities. Special attention is given to the biogeographic observations made for the Falkland Plateau (DSDP Legs 36 and 71) and the Weddell Sea (ODP Leg 113). Both areas have yielded valuable Lower Cretaceous fossil records of the circumantarctic high latitudes. In general, the Neocomian fossil record from DSDP and ODP sites off northwestern Australia has important southern high-latitude affinities and weak Tethyan influence. The same is true for the pelagic lithofacies: radiolarian chert and/or nannofossil limestone, dominant in the Tethyan Lower Cretaceous, are minor lithologies in the Exmouth-Argo sites. These observations, together with the young age of the Argo crust and plate tectonic considerations, suggest that the Argo Basin was not part of the Tethys Realm. The biogeography of the Neocomian radiolarian and nannofossil assemblages suggests opening of a seaway during the Berriasian that connected the circumantarctic area with the Argo Basin, which resulted in the influx of southern high-latitude waters. This conclusion constrains the initial fit and break-up history of Gondwana. Our results favor the loose fit of the western Australian margin with southeast India by Ricou et al. (1990), which accounts for a deeper water connection with the Weddell-Mozambique basins via drowned marginal plateaus as early as the Berriasian. In fits of the du Toit-type (1937), India would remain attached to Antarctica, at least until the late Valanginian, making such a connection impossible. After the Barremian, increasing Tethyan influence is evident in all fossil groups, although southern high-latitude taxa are still present. Biogeographic domains, such as the southern extension of Nannoconus and Ticinella suggest paleolatitudes of about 50°S for the Exmouth-Argo area. Alternatively, if paleolatitudes of about 35° are accepted, these biogeographic limits were displaced northward at least 15° along Australia in comparison to the southern Atlantic. In this case, the proto-circumantarctic current was deflected northward into an eastern boundary current off Australia and carried circumantarctic cold water into the middle latitudes. Late Aptian/early Albian time is characterized by mixing of Tethyan and southern faunal elements and a significant gradient in Albian surface-water temperatures over 10° latitude along the Australian margin, as indicated by planktonic foraminifers. Both phenomena may be indicative of convergence of temperate and antarctic waters near the Australian margin. High fertility conditions, reflected by radiolarian cherts, are suggestive of coastal upwelling during that time

Early Cretaceous Biogeographic and Oceanographic Synthesis of Leg 123 (off Northwestern Australia)

Biogeographic observations made by Leg 123 shipboard paleontologists for Lower Cretaceous nannofossils, foraminifers, radiolarians, belemnites, and inoceramids are combined in this chapter to evaluate the paleoceanographic history of the northwestern Australian margin and adjacent basins. Each fossil group is characterized at specific intervals of Cretaceous time and compared with data from Tethyan and Southern Hemisphere high-latitude localities. Special attention is given to the biogeographic observations made for the Falkland Plateau (DSDP Legs 36 and 71) and the Weddell Sea (ODP Leg 113). Both areas have yielded valuable Lower Cretaceous fossil records of the circumantarctic high latitudes. In general, the Neocomian fossil record from DSDP and ODP sites off northwestern Australia has important southern high-latitude affinities and weak Tethyan influence. The same is true for the pelagic lithofacies: radiolarian chert and/or nannofossil limestone, dominant in the Tethyan Lower Cretaceous, are minor lithologies in the Exmouth-Argo sites. These observations, together with the young age of the Argo crust and plate tectonic considerations, suggest that the Argo Basin was not part of the Tethys Realm. The biogeography of the Neocomian radiolarian and nannofossil assemblages suggests opening of a seaway during the Berriasian that connected the circumantarctic area with the Argo Basin, which resulted in the influx of southern high-latitude waters. This conclusion constrains the initial fit and break-up history of Gondwana. Our results favor the loose fit of the western Australian margin with southeast India by Ricou et al. (1990), which accounts for a deeper water connection with the Weddell-Mozambique basins via drowned marginal plateaus as early as the Berriasian. In fits of the du Toit-type (1937), India would remain attached to Antarctica, at least until the late Valanginian, making such a connection impossible. After the Barremian, increasing Tethyan influence is evident in all fossil groups, although southern high-latitude taxa are still present. Biogeographic domains, such as the southern extension of Nannoconus and Ticinella suggest paleolatitudes of about 50°S for the Exmouth-Argo area. Alternatively, if paleolatitudes of about 35° are accepted, these biogeographic limits were displaced northward at least 15° along Australia in comparison to the southern Atlantic. In this case, the proto-circumantarctic current was deflected northward into an eastern boundary current off Australia and carried circumantarctic cold water into the middle latitudes. Late Aptian/early Albian time is characterized by mixing of Tethyan and southern faunal elements and a significant gradient in Albian surface-water temperatures over 10° latitude along the Australian margin, as indicated by planktonic foraminifers. Both phenomena may be indicative of convergence of temperate and antarctic waters near the Australian margin. High fertility conditions, reflected by radiolarian cherts, are suggestive of coastal upwelling during that time

Plasminogen activation triggers transthyretin amyloidogenesis in vitro

Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro. In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo. Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro. Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo. Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation

Dupilumab demonstrates rapid and consistent improvement in extent and signs of atopic dermatitis across all anatomical regions in pediatric patients 6 years of age and older

Introduction In phase III trials in adolescents and children with atopic dermatitis (AD), dupilumab significantly decreased global disease severity. However, the effects of dupilumab on the extent and signs of AD across different anatomical regions were not reported. Here we characterize the efficacy of dupilumab in improving the extent and signs of AD across four different anatomical regions in children and adolescents. Methods A post hoc subset analysis was performed using data from two randomized, double-blind, placebo-controlled, international multicenter, phase III trials of dupilumab therapy in adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD and children aged ≥ 6 to < 12 years with severe AD. Endpoints included mean percentage change in Eczema Area and Severity Index (EASI) signs (erythema, edema/papulation, excoriation, lichenification) and extent of AD (measured by percentage of body surface area [% BSA] involvement) from baseline to week 16 across four anatomical regions (head and neck, trunk, upper extremities, lower extremities). Results Dupilumab improved both the extent and severity of AD signs across the four anatomical regions. Improvements were shown to be similar across the four anatomical regions for % BSA involvement and for reduction in EASI signs. Improvements in all signs were seen early, within the first 4 weeks of treatment, and were sustained through week 16, across all regions. Conclusions In pediatric patients 6 years of age and older, treatment with dupilumab resulted in rapid and consistent improvement in the extent and signs of AD across all anatomical regions. ClinicalTrials.gov Identifiers LIBERTY AD ADOL (NCT03054428) and LIBERTY AD PEDS (NCT03345914)

Plasminogen activation triggers transthyretin amyloidogenesis in vitro

Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro. In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo. Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro. Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo. Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation

A specific nanobody prevents amyloidogenesis of D76N \u3b22-microglobulin in vitro and modifies its tissue distribution in vivo

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of \u3b22-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type \u3b22-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The \u3b22-microglobulin -binding nanobody, Nb24, more potently inhibits D76N \u3b22-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In \u3b22-microglobulin knock out mice, the D76N \u3b22-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type \u3b22-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis