Relative sea-level rise around East Antarctica during Oligocene glaciation

During the middle and late Eocene (∼48-34 Myr ago), the Earth's climate cooled and an ice sheet built up on Antarctica. The stepwise expansion of ice on Antarcticainduced crustal deformation and gravitational perturbations around the continent. Close to the ice sheet, sea level rosedespite an overall reduction in the mass of the ocean caused by the transfer of water to the ice sheet. Here we identify the crustal response to ice-sheet growth by forcing a glacial-hydro isostatic adjustment model with an Antarctic ice-sheet model. We find that the shelf areas around East Antarctica first shoaled as upper mantle material upwelled and a peripheral forebulge developed. The inner shelf subsequently subsided as lithosphere flexure extended outwards from the ice-sheet margins. Consequently the coasts experienced a progressive relative sea-level rise. Our analysis of sediment cores from the vicinity of the Antarctic ice sheet are in agreement with the spatial patterns of relative sea-level change indicated by our simulations. Our results are consistent with the suggestion that near-field processes such as local sea-level change influence the equilibrium state obtained by an icesheet grounding line

Influence of management practice on the microbiota of a critically endangered species: A longitudinal study of kākāpō chick faeces and associated nest litter

Background: The critically endangered kākāpō is a flightless, nocturnal parrot endemic to Aotearoa New Zealand. Recent efforts to describe the gastrointestinal microbial community of this threatened herbivore revealed a low-diversity microbiota that is often dominated by Escherichia-Shigella bacteria. Given the importance of associated microbial communities to animal health, and increasing appreciation of their potential relevance to threatened species conservation, we sought to better understand the development of this unusual gut microbiota profile. To this end, we conducted a longitudinal analysis of faecal material collected from kākāpō chicks during the 2019 breeding season, in addition to associated nest litter material. Results: Using an experimental approach rarely seen in studies of threatened species microbiota, we evaluated the impact of a regular conservation practice on the developing kākāpō microbiota, namely the removal of faecal material from nests. Artificially removing chick faeces from nests had negligible impact on bacterial community diversity for either chicks or nests (p > 0.05). However, the gut microbiota did change significantly over time as chick age increased (p < 0.01), with an increasing relative abundance of Escherichia-Shigella coli over the study period and similar observations for the associated nest litter microbiota (p < 0.01). Supplementary feeding substantially altered gut bacterial diversity of kākāpō chicks (p < 0.01), characterised by a significant increase in Lactobacillus bacteria. Conclusions: Overall, chick age and hand rearing conditions had the most marked impact on faecal bacterial communities. Similarly, the surrounding nest litter microbiota changed significantly over time since a kākāpō chick was first placed in the nest, though we found no evidence that removal of faecal material influenced the bacterial communities of either litter or faecal samples. Taken together, these observations will inform ongoing conservation and management of this most enigmatic of bird species

Senolytic vaccination: a new mandate for cardiovascular health?

Senescent cell accumulation is increasingly associated with a number of age-related cardiovascular diseases. Now, a new manuscript in Nature Aging suggests that a novel vaccine-based strategy might provide a targeted method to eliminate the senescent cell population

Novel PDE4 inhibitors derived from Chinese medicine forsythia.

Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response

Forsythin is an inhibitor of PDE4.

<p><b>A–C.</b> The chemical structure of Forsythin extracted from <i>Forsythia suspensa</i> seeds. Forsythin is an o-linked β-D-glucopyranosylated lignin that can be hydrolyzed (Red line). <b>D.</b> Predicted docking site of Forsythin with PDE4. <b>E.</b> Predicted residue electrostatic and van der Waals interactions between PDE4 amino acids and Forsythin. Using ZINCPharmer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115937#pone.0115937-Koes1" target="_blank">[24]</a>, a pharmacophore model was generated (upper left) and used to screen the lead compounds from an 18.3 million purchasable compound library.</p

Tested compounds reduce TNF secretion in LPS stimulated mouse RAW264.7 and human PBMCs.

<p><b>A.</b> 5×10⁵ RAW264.7 cells were seeded in 96 wells for 18 h. Cells were primed with compounds at different concentration for 3 h before treated with LPS (1 ng/ml) for additional 8 h. TNF cytokine releases were monitored by ELISA. <b>B.</b> PBMC (0.2 ml at 1×10⁵/ml) were primed with compounds at different concentration for 3 h before treated with LPS (1 ng/ml) for additional 8 h. TNF cytokine releases were monitored by ELISA. % of TNF secretion were calculated and graphed. <b>C.</b> Summary of compound IC₅₀. The data represent <i>n</i> = 3–6 experiments.</p

PDE4 inhibitors lessen cytokine storm induced by LPS septic shock.

<p>C57/BL6 mice were administered i.p. nothing (CON), vehicle, 10 ug/kg, 100 ug/kg, 1 mg/kg or 10 mg/kg of compounds 6, 7 or 9. Mice were given LPS (<i>E. coli,</i> 100 µg) 10 min later through an i.p. injection. 2 h later mice were euthanized using pentobarbital and blood was collected for IL-6 and TNF measurements. Shown in panel <b>A–B</b> is the % inhibition of cytokine levels as a function of drug dose. The data represent <i>n</i> = 3 mice/group at each dose. C57/BL6 mice were also pretreated with compound 5, 6, 7 or 9 at 1 mg/kg. Mice were given LPS (<i>E. coli,</i> 100 µg) 18 h later through an i.p. injection. 2 h later the mice were euthanized using pentobarbital and blood was collected for IL-6 and TNF measurements (<b>C–D</b>). The data represent <i>n</i> = 4–6 mice/group, *<i>P</i><0.05 versus vehicle.</p

Tested compounds exhibit high potency and selectivity towards PDE4.

<p>For the PDE activity assay, all test compounds were diluted in DMSO with final concentrations in each assay of 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 µM. For the PDE4 activity assay, 10 mU of purified PDE4 (Millipore) was used per reaction. Compounds 6, 7, 9 and 13 (blue underline) were further tested in PDE3, 5, 7, 10 activity assays in which 25 mU of purified enzyme was used per reaction. Summary of compound IC₅₀ in lower right corner.</p