Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

A pulse of mid-Pleistocene rift volcanism in Ethiopia at the dawn of modern humans

The Ethiopian Rift Valley hosts the longest record of human co-existence with volcanoes on Earth, however, current understanding of the magnitude and timing of large explosive eruptions in this region is poor. Detailed records of volcanism are essential for interpreting the palaeoenvironments occupied by our hominin ancestors; and also for evaluating the volcanic hazards posed to the 10 million people currently living within this active rift zone. Here we use new geochronological evidence to suggest that a 200 km-long segment of rift experienced a major pulse of explosive volcanic activity between 320 and 170 ka. During this period, at least four distinct volcanic centres underwent large-volume (>10 km3) caldera-forming eruptions, and eruptive fluxes were elevated five times above the average eruption rate for the past 700 ka. We propose that such pulses of episodic silicic volcanism would have drastically remodelled landscapes and ecosystems occupied by early hominin populations

Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI

Mesenchymal cell survival in airway and interstitial pulmonary fibrosis

Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis

Inflammasome-Mediated IL-1β Production in Humans with Cystic Fibrosis

Inflammation and infection are major determinants of disease severity and consequently, the quality of life and outcome for patients with cystic fibrosis (CF). Interleukin-1 beta (IL-1β) is a key inflammatory mediator. Secretion of biologically active IL-1β involves inflammasome-mediated processing. Little is known about the contribution of IL-1β and the inflammasomes in CF inflammatory disease. This study examines inflammasome-mediated IL-1β production in CF bronchial epithelial cell lines and human patients with CF.Bronchial epithelial cell lines were found to produce negligible amounts of basal or stimulated IL-1β compared to hematopoeitic cells and they did not significantly upregulate caspase-1 activity upon inflammasome stimulation. In contrast, peripheral blood mononuclear cells (PBMCs) from both CF and healthy control subjects produced large amounts of IL-1β and strongly upregulated caspase-1 activity upon inflammasome stimulation. PBMCs from CF patients and controls displayed similar levels of caspase-1 activation and IL-1β production when stimulated with inflammasome activators. This IL-1β production was dependent on NF-κB activity and could be enhanced by priming with LPS. Finally, chemical inhibition of CFTR activity in control PBMCs and THP-1 cells did not significantly alter IL-1β or IL-8 production in response to P. aeruginosa.Hematopoeitic cells appear to be the predominant source of inflammasome-induced pro-inflammatory IL-1β in CF. PBMCs derived from CF subjects display preserved inflammasome activation and IL-1β secretion in response to the major CF pathogen Pseudomonas aeruginosa. However, our data do not support the hypothesis that increased IL-1β production in CF subjects is due to an intrinsic increase in NF-κB activity through loss of CFTR function

Metabolomic Analysis in Severe Childhood Pneumonia in The Gambia, West Africa: Findings from a Pilot Study

Pneumonia remains the leading cause of death in young children globally and improved diagnostics are needed to better identify cases and reduce case fatality. Metabolomics, a rapidly evolving field aimed at characterizing metabolites in biofluids, has the potential to improve diagnostics in a range of diseases. The objective of this pilot study is to apply metabolomic analysis to childhood pneumonia to explore its potential to improve pneumonia diagnosis in a high-burden setting. and Random Forests (RF). ‘Unsupervised’ (blinded) data were analyzed by Principal Component Analysis (PCA), while ‘supervised’ (unblinded) analysis was by Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Projection to Latent Structures (OPLS). Potential markers were extracted from S-plots constructed following analysis with OPLS, and markers were chosen based on their contribution to the variation and correlation within the data set. The dataset was additionally analyzed with the machine-learning algorithm RF in order to address issues of model overfitting and markers were selected based on their variable importance ranking. Unsupervised PCA analysis revealed good separation of pneumonia and control groups, with even clearer separation of the groups with PLS-DA and OPLS analysis. Statistically significant differences (p<0.05) between groups were seen with the following metabolites: uric acid, hypoxanthine and glutamic acid were higher in plasma from cases, while L-tryptophan and adenosine-5′-diphosphate (ADP) were lower; uric acid and L-histidine were lower in urine from cases. The key limitation of this study is its small size.Metabolomic analysis clearly distinguished severe pneumonia patients from community controls. The metabolites identified are important for the host response to infection through antioxidant, inflammatory and antimicrobial pathways, and energy metabolism. Larger studies are needed to determine whether these findings are pneumonia-specific and to distinguish organism-specific responses. Metabolomics has considerable potential to improve diagnostics for childhood pneumonia