Transforming Growth Factor ��1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

Exogenous or endogenous β₂-adrenergic receptor agonists enhance alveolar epithelial fluid transport via a cAMP-dependent mechanism that protects the lungs from alveolar flooding in acute lung injury. However, impaired alveolar fluid clearance is present in most of the patients with acute lung injury and is associated with increased mortality, although the mechanisms responsible for this inhibition of the alveolar epithelial fluid transport are not completely understood. Here, we found that transforming growth factor β1 (TGF-β1), a critical mediator of acute lung injury, inhibits β₂-adrenergic receptor agonist-stimulated vectorial fluid and Cl⁻ transport across primary rat and human alveolar epithelial type II cell monolayers. This inhibition is due to a reduction in the cystic fibrosis transmembrane conductance regulator activity and biosynthesis mediated by a phosphatidylinositol 3-kinase (PI3K)-dependent heterologous desensitization and down-regulation of the β₂-adrenergic receptors. Consistent with these in vitro results, inhibition of the PI3K pathway or pretreatment with soluble chimeric TGF-β type II receptor restored β₂-adrenergic receptor agonist-stimulated alveolar epithelial fluid transport in an in vivo model of acute lung injury induced by hemorrhagic shock in rats. The results demonstrate a novel role for TGF-β1 in impairing the β- adrenergic agonist-stimulated alveolar fluid clearance in acute lung injury, an effect that could be corrected by using PI3K inhibitors that are safe to use in humans.     

Late Miocene Survival of a Hyper-Longirostrine Dolphin and the Neogene to Recent Evolution of Rostrum Proportions Among Odontocetes

Hyper-longirostry, the character of having extremely elongated rostra, emerged in the early and middle Miocene among several different clades of echolocating toothed whales (odontocetes) followed by a rapid decline near the end of the middle Miocene, and postdated by a much lower number of occurrences in the late Miocene and Pliocene and a complete absence among extant odontocetes. New finds of unreworked fossils of Xiphiacetus cristatus (Eurhinodelphinidae) in the middle Tortonian Diest Formation in Belgium (9.54–8.8 Ma) allow for the documentation of the survival of a hyper-longirostrine dolphin into the early late Miocene. An extensive dataset of the rostral index (calculated as the ratio between rostral length and condylobasal length) of Neogene and extant odontocetes is compiled and presented here, which facilitates discussion of evolutionary trends of rostrum proportions during a time period spanning 23 million years. Of interest, the iterative survival into the late Miocene of a single different species of hyper-longirostrine dolphins in a number of paleogeographic regions (North Sea Basin, Atlantic Coastal Plain, and probably the southeastern Pacific) is noted, whereas hyper-longirostrine morphologies only seem to re-appear by the late Messinian in the Northeastern Pacific. A correlation between this pattern and a decrease in habitat size for coastal to estuarine dolphins linked to a major sea level drop is tentatively proposed; such a process may also have played a role in the ecological shift in several dolphin families to freshwater habitats.

     

KGF‐2 targets alveolar epithelia and capillary endothelia to reduce high altitude pulmonary oedema in rats

High altitude pulmonary oedema (HAPE) severely affects non‐acclimatized individuals and is characterized by alveolar flooding with protein‐ rich oedema as a consequence of blood‐gas barrier disruption. Limited choice for prophylactic treatment warrants effective therapy against HAPE. Keratinocyte growth factor‐2 (KGF‐2) has shown efficiency in preventing alveolar epithelial cell DNA damages in vitro. In the current study, the effects of KGF‐2 intratracheal instillation on mortality, lung liquid balance and lung histology were evaluated in our previously developed rat model of HAPE. We found that pre‐treatment with KGF‐2 (5 mg/kg) significantly decreased mortality, improved oxygenation and reduced lung wet‐to‐dry weight ratio by preventing alveolar‐capillary barrier disruption demonstrated by histological examination and increasing alveolar fluid clearance up to 150%. In addition, KGF‐2 significantly inhibited decrease of transendothelial permeability after exposure to hypoxia, accompanied by a 10‐fold increase of Akt activity and inhibited apoptosis in human pulmonary microvascular endothelial cells, demonstrating attenuated endothelial apoptosis might contribute to reduction of endothelial permeability. These results showed the efficacy of KGF‐2 on inhibition of endothelial cell apoptosis, preservation of alveolar‐capillary barrier integrity and promotion of pulmonary oedema absorption in HAPE. Thus, KGF‐2 may represent a potential drug candidate for the prevention of HAPE.     

Type-Maastrichtian gastropod faunas show rapid ecosystem recovery following the Cretaceous–Palaeogene boundary catastrophe

The study of the global mass extinction event at the Cretaceous–Palaeogene (K/Pg) boundary can aid in understanding patterns of selective extinction, and survival and dynamics of ecosystem recovery. Outcrops in the Maastrichtian type area (south-east Netherlands, north-east Belgium) comprise a stratigraphically expanded K/Pg boundary succession that offers a unique opportunity to study marine ecosystem recovery within the first few thousand years following the mass extinction event. A quantitative analysis was performed on systematically sampled macrofossils of the topmost Maastrichtian and lowermost Danian strata at the former Ankerpoort-Curfs quarry (Geulhem), which represent ‘snapshots’ of the latest Cretaceous and earliest Palaeogene marine ecosystems, respectively. Molluscs in particular are diverse and abundant in the studied succession. Regional ecosystem changes across the K/Pg boundary are relatively minor, showing a decline in suspension feeders, accompanied by an ecological shift to endobenthic molluscs. The earliest Paleocene gastropod assemblage retains many ‘Maastrichtian’ features and documents a fauna that temporarily survived into the Danian. The shallow, oligotrophic carbonate platform in this area was inhabited by taxa that were adapted to low nutrient levels and resistant to starvation. As a result, the local taxa were less affected by the short-lived detrimental conditions related to K/Pg boundary perturbations, such as darkness, cooling, starvation and ocean acidification. This resulted in relatively high survival rates, which enabled rapid recolonization and recovery of marine faunas in the Maastrichtian type area.     

Differentiation of epithelial Na+ channel function. An in vitro model

Confluent monolayers of epithelial cells grown on nonporous support form fluid-filled hemicysts called domes, which reflect active ion transport across the epithelium. Clara-like H441 lung adenocarcinoma cells grown on glass supports and exposed to 50 nM dexamethasone developed domes in a time-dependent fashion. Uplifting of small groups of cells occurred within 6-12 h, well formed domes appeared between 24 and 48 h, and after 7 days, individual domes started to merge. Cells inside of domes compared with those outside domes, or with monolayers not exposed to dexamethasone, differed by higher surfactant production, an increased cytokeratin expression, and the localization of claudin-4 proteins to the plasma membrane. In patch clamp studies, amiloride-blockable sodium currents were detected exclusively in cells inside domes, whereas in cells outside of domes, sodium crossed the membrane through La3+-sensitive nonspecific cation channels. Cells grown on permeable support without dexamethasone expressed amiloride-sensitive currents only after tight electrical coupling was achieved (transepithelial electrical resistance (R(t)) > 1 kilohm). In real-time quantitative PCR experiments, the addition of dexamethasone increased the content of claudin-4, occludin, and Na+ channel gamma-subunit (gamma-ENaC) mRNAs by 1.34-, 1.32-, and 1.80-fold, respectively, after 1 h and was followed by an increase at 6 h in the content of mRNA of alpha- and beta-ENaC and of alpha1- and beta1-Na,K-ATPase. In the absence of dexamethasone, neither change in gene expression nor cell uplifting was observed. Our data suggest that during epithelial differentiation, coordinated expression of tight junction proteins precedes the development of vectorial transport of sodium, which in turn leads to the fluid accumulation in basolateral spaces that is responsible for dome formation.     

Recent advances in heteromorph ammonoid palaeobiology

Heteromorphs are ammonoids forming a conch with detached whorls (open coiling) or non-planispiral coiling. Such aberrant forms appeared convergently four times within this extinct group of cephalopods. Since Wiedmann's seminal paper in this journal, the palaeobiology of heteromorphs has advanced substantially. Combining direct evidence from their fossil record, indirect insights from phylogenetic bracketing, and physical as well as virtual models, we reach an improved understanding of heteromorph ammonoid palaeobiology. Their anatomy, buoyancy, locomotion, predators, diet, palaeoecology, and extinction are discussed. Based on phylogenetic bracketing with nautiloids and coleoids, heteromorphs like other ammonoids had 10 arms, a well-developed brain, lens eyes, a buccal mass with a radula and a smaller upper as well as a larger lower jaw, and ammonia in their soft tissue. Heteromorphs likely lacked arm suckers, hooks, tentacles, a hood, and an ink sac. All Cretaceous heteromorphs share an aptychus-type lower jaw with a lamellar calcitic covering. Differences in radular tooth morphology and size in heteromorphs suggest a microphagous diet. Stomach contents of heteromorphs comprise planktic crustaceans, gastropods, and crinoids, suggesting a zooplanktic diet. Forms with a U-shaped body chamber (ancylocone) are regarded as suspension feeders, whereas orthoconic forms additionally might have consumed benthic prey. Heteromorphs could achieve near-neutral buoyancy regardless of conch shape or ontogeny. Orthoconic heteromorphs likely had a vertical orientation, whereas ancylocone heteromorphs had a near-horizontal aperture pointing upwards. Heteromorphs with a U-shaped body chamber are more stable hydrodynamically than modern Nautilus and were unable substantially to modify their orientation by active locomotion, i.e. they had no or limited access to benthic prey at adulthood. Pathologies reported for heteromorphs were likely inflicted by crustaceans, fish, marine reptiles, and other cephalopods. Pathologies on Ptychoceras corroborates an external shell and rejects the endocochleate hypothesis. Devonian, Triassic, and Jurassic heteromorphs had a preference for deep-subtidal to offshore facies but are rare in shallow-subtidal, slope, and bathyal facies. Early Cretaceous heteromorphs preferred deep-subtidal to bathyal facies. Late Cretaceous heteromorphs are common in shallow-subtidal to offshore facies. Oxygen isotope data suggest rapid growth and a demersal habitat for adult Discoscaphites and Baculites. A benthic embryonic stage, planktic hatchlings, and a habitat change after one whorl is proposed for Hoploscaphites. Carbon isotope data indicate that some Baculites lived throughout their lives at cold seeps. Adaptation to a planktic life habit potentially drove selection towards smaller hatchlings, implying high fecundity and an ecological role of the hatchlings as micro- and mesoplankton. The Chicxulub impact at the Cretaceous/Paleogene (K/Pg) boundary 66 million years ago is the likely trigger for the extinction of ammonoids. Ammonoids likely persisted after this event for 40–500 thousand years and are exclusively represented by heteromorphs. The ammonoid extinction is linked to their small hatchling sizes, planktotrophic diets, and higher metabolic rates than in nautilids, which survived the K/Pg mass extinction event.