Intensive Care Ethics in Evolution

The ethics of treating the seriously and critically ill have not been static throughout the ages. Twentieth century medicine has inherited from the nineteenth century a science which places an inappropriate weight on diagnosis over prognosis and management, combined with a seventeenth century duty to prolong life. However other earlier ethical traditions, both Hippocratic and Christian, respected both the limitations of medicine and emphasised the importance of prognosis. This paper outlines some of the historical precedents for the treatment of the critically ill, and also how the current paradigm limits clinical practice and causes ethical tensions. An understanding that other paradigms have been ethically acceptable in the past allows wider consideration and acceptance of alternatives for the future. However future alternatives will also have to address the role of technology, given its importance in this area of medicine.     

Dynamic Localization of Tat Protein Transport Machinery Components in Streptomyces coelicolor

The Tat pathway transports folded proteins across the bacterial cytoplasmic membrane and is a major route of protein export in the Streptomyces genus of bacteria. In this study, we have examined the localization of Tat components in the model organism Streptomyces coelicolor by constructing enhanced green fluorescent protein (eGFP) and mCherry fusions with the TatA, TatB, and TatC proteins. All three components colocalized dynamically in the vegetative hyphae, with foci of each tagged protein being prominent at the tips of emerging germ tubes and of the vegetative hyphae, suggesting that this may be a primary site of Tat secretion. Time-lapse imaging revealed that localization of the Tat components was highly dynamic during tip growth and again demonstrated a strong preference for apical sites in growing hyphae. During aerial hypha formation, TatA-eGFP and TatB-eGFP fusions relocalized to prespore compartments, indicating repositioning of Tat components during the Streptomyces life cycle.     

WIKI4, a Novel Inhibitor of Tankyrase and Wnt/?-Catenin Signaling

The Wnt/ß-catenin signaling pathway controls important cellular events during development and often contributes to disease when dysregulated. Using high throughput screening we have identified a new small molecule inhibitor of Wnt/ß-catenin signaling, WIKI4. WIKI4 inhibits expression of ß-catenin target genes and cellular responses to Wnt/ß-catenin signaling in cancer cell lines as well as in human embryonic stem cells. Furthermore, we demonstrate that WIKI4 mediates its effects on Wnt/ß-catenin signaling by inhibiting the enzymatic activity of TNKS2, a regulator of AXIN ubiquitylation and degradation. While TNKS has previously been shown to be the target of small molecule inhibitors of Wnt/ß-catenin signaling, WIKI4 is structurally distinct from previously identified TNKS inhibitors.     

Both endonucleolytic and exonucleolytic cleavage mediate ITS1 removal during human ribosomal RNA processing

Human ribosome production is up-regulated during tumorogenesis and is defective in many genetic diseases (ribosomopathies). We have undertaken a detailed analysis of human precursor ribosomal RNA (pre-rRNA) processing because surprisingly little is known about this important pathway. Processing in internal transcribed spacer 1 (ITS1) is a key step that separates the rRNA components of the large and small ribosomal subunits. We report that this was initiated by endonuclease cleavage, which required large subunit biogenesis factors. This was followed by 3′ to 5′ exonucleolytic processing by RRP6 and the exosome, an enzyme complex not previously linked to ITS1 removal. In contrast, RNA interference–mediated knockdown of the endoribonuclease MRP did not result in a clear defect in ITS1 processing. Despite the apparently high evolutionary conservation of the pre-rRNA processing pathway and ribosome synthesis factors, each of these features of human ITS1 processing is distinct from those in budding yeast. These results also provide significant insight into the links between ribosomopathies and ribosome production in human cells.     

Threshold response of Madagascar's littoral forest to sea-level rise

Aim Coastal biodiversity hotspots are globally threatened by sea‐level rise. As such it is important to understand how ecosystems resist, respond and adapt to sea‐level rise. Using pollen, geochemistry, charcoal and diatom records in conjunction with previously published palaeoclimatic records, we investigated the mechanism, interactions and ecosystem response and resilience of Madagascar's littoral forest to late Holocene sea‐level rise. Location Sediment sequences were collected along the south‐east coast of Madagascar in two adjacent habitats in Mandena; the highly diverse littoral forest fragment and species‐poor Erica‐matrix. Methods We used a multi‐proxy approach to investigate the relative influence of environmental changes on the littoral ecosystem. We reconstructed past vegetation and fire dynamics over the past 6500 years at two sites in the littoral forest using fossil pollen and macrofossil charcoal contained in sedimentary sequences. Alongside these records we reconstructed past marine transgressions from the same sedimentary sequences using geochemical analyses, and a salinity and drought index through the analysis of fossil diatoms. Results Our findings indicated that it was the synergistic effect of sea‐level rise coupled with rainfall deficits that triggered a threshold event with a switch from two types of littoral forest (an open Uapaca forest and a closed littoral forest fragment) to an Erica–Myrica heath/grassland occurring in approximately less than 100 years. Resilience to sea‐level rise differed in the two adjacent habitats, suggesting that the littoral forest fragment was more resilient to the impacts of sea‐level change and aridity than the open Uapaca woodland. Conclusions We demonstrated that the littoral ecosystem was influenced by late Holocene sea‐level rise and climatic desiccation. While climate change‐integrated conservation strategies address the effects of climate change on species distribution and dispersal, our work suggests that more attention should be paid to the impacts of interactive climatic variables that affect ecosystem thresholds.