Many organisms occupy heterogeneous landscapes that contain both barriers to movement as well as corridors that facilitate dispersal. The extent to which such features determine population connectivity will depend on the mechanisms utilized by organisms to disperse. Here we examined the interaction between landscape structure and dispersal in the endemic aquatic snail, Fonscochlea accepta, in the fragmented artesian spring ecosystem of arid central Australia. We used frequentist and Bayesian analyses of microsatellite data to identify population structure and immigration for 1130 snails sampled from 50 springs across an entire spring complex. We introduce a modified isolation-by-distance analysis to test hypotheses about how populations are clustered and to distinguish the most likely dispersal pathways within and between those clusters. Highly significant differences in F(ST) values and significant isolation-by-distance patterns were detected among springs across the entire complex, while Bayesian assignment tests revealed the presence of two hierarchical levels of spring clustering. Clusters were defined by the spatial aggregation of springs, dynamic aquatic habitat connections between springs and the ecology of the snails. Bayesian immigrant identification and our modified isolation-by-distance analysis revealed that dispersal occurs at two geographical scales via two very different mechanisms. Short range dispersal (usually or= 3 km) is likely facilitated by an animal vector (phoresy). These results underline the importance of both dispersal mode and landscape structure in influencing connectivity rates and patterns among populations.

Malignant mesothelioma is a form of cancer that is highly resistant to conventional cancer therapy for which no major therapeutic advances have been introduced. Here, we identify gremlin-1, a known bone morphogenetic protein inhibitor crucial for embryonic development, as a potential therapeutic target for mesothelioma. We found high expression levels of gremlin-1 in the mesothelioma tumor tissue, as well as in primary mesothelioma cells cultured from pleural effusion samples. Downregulation of gremlin-1 expression by siRNA-mediated silencing in a mesothelioma cell line inhibited cell proliferation. This was associated with downregulation of the transcription factor slug as well as mesenchymal proteins linked to cancer epithelial-to-mesenchymal transition. Further, resistance to paclitaxel-induced cell death was associated with high gremlin-1 and slug expression. Treatment of gremlin-1-silenced mesothelioma cells with paclitaxel or pemetrexed resulted in efficient loss of cell survival. Finally, our data suggest that concomitant upregulation of fibrillin-2 in mesothelioma provides a mechanism for extracellular localization of gremlin-1 to the tumor microenvironment. This was supported by the demonstration of interactions between gremlin-1, and fibrillin-1 and -2 peptides as well as by colocalization of gremlin-1 to fibrillin microfibrils in cells and tumor tissue samples. Our data suggest that gremlin-1 is also a potential target for overcoming drug resistance in mesothelioma.

Interleukin- 33 (IL-33) is an epithelial-derived cytokine that initiates type 2 immune responses to allergens, though whether IL-33 has the ability to modify responses to respiratory viral infections remains unclear. This study aimed to investigate the effects of IL-33 on rhinovirus (RV)-induced immune responses by circulating leukocytes from people with allergic asthma, and how this response may differ from non-allergic controls. Our experimental approach involved co-exposing peripheral blood mononuclear cells to IL-33 and RV in order to model how the functions of virus-responsive lymphocytes could be modified after recruitment to an airway environment enriched in IL-33. In the current study, IL-33 enhanced RV-induced IL-5 and IL-13 release by cells from people with allergic asthma, but had no effect on IL-5 and IL-13 production by cells from healthy donors. In asthmatic individuals, IL-33 also enhanced mRNA and surface protein expression of ST2 (the IL-33 receptor IL1RL1), while soluble ST2 concentrations were low. In contrast, IL-33 had no effect on mRNA and surface expression of ST2 in healthy individuals. In people with allergic asthma, RV-activated ST2+ innate lymphoid cells (ST2+ILC) were the predominant source of IL-33 augmented IL-13 release. In contrast, RV-activated natural killer cells (NK cells) were the predominant source of IL-33 augmented IFNγ release in healthy individuals. This suggests that the effects of IL-33 on the cellular immune response to RV differ between asthmatic and healthy individuals. These findings provide a mechanism by which RV infections and IL-33 might interact in asthmatic individuals to exacerbate type 2 immune responses and allergic airway inflammation.

The role of disturbance in the promotion of biological heterogeneity is widely recognised and occurs at a variety of ecological and evolutionary scales. However, within species, the impact of disturbances that decimate populations are neither predicted nor known to result in conditions that promote genetic diversity. Directly examining the population genetic consequences of catastrophic disturbances however, is rarely possible, as it requires both longitudinal genetic data sets and serendipitous timing. Our long-term study of the endemic aquatic invertebrates of the artesian spring ecosystem of arid central Australia has presented such an opportunity. Here we show a catastrophic flood event, which caused a near total population crash in an aquatic snail species (Fonscochlea accepta) endemic to this ecosystem, may have led to enhanced levels of within species genetic diversity. Analyses of individuals sampled and genotyped from the same springs sampled both pre (1988–1990) and post (1995, 2002–2006) a devastating flood event in 1992, revealed significantly higher allelic richness, reduced temporal population structuring and greater effective population sizes in nearly all post flood populations. Our results suggest that the response of individual species to disturbance and severe population bottlenecks is likely to be highly idiosyncratic and may depend on both their ecology (whether they are resilient or resistant to disturbance) and the stability of the environmental conditions (i.e. frequency and intensity of disturbances) in which they have evolved.

Viral respiratory infections are usually benign but can trigger asthma exacerbations. The factors associated with upper respiratory tract infection (cold) frequency are not fully understood, nor is it clear whether such factors differ between women and men.To determine which immunological and clinical variables associate with the frequency of self-reported respiratory infections (colds), 150 asthma cases and 151 controls were recruited. Associations between antiviral immune response variables – TLR7/8 gene expression, plasmacytoid dendritic cell (pDC) numbers and interferon-alpha, TNF and IL-12 production – and asthma were then examined that might explain cold frequency.People with asthma cases reported more colds per year (median 3 versus 2, p<0.001) and had lower baseline TLR7 gene expression (odds ratio (OR)=0.12, p=0.02) than controls. Associations between many variables and cold frequency differed between women and men. In women, high blood neutrophil counts (beta=0.096, p=0.002), and younger age (beta= −0.017, p<0.001), but not exposure to children, were independently associated with more frequent colds. In men, low TLR7 expression (beta= −0.96, p=0.041) and high CLEC4C gene expression (a marker of pDC; beta=0.88, p=0.008) were independently associated with more frequent colds. Poor asthma symptom control was independently associated with reduced TLR8 gene expression (beta= −1.4, p=0.036) and high BMI (beta=0.041, p=0.004).Asthma, age and markers of inflammation and antiviral immunity in peripheral blood are associated with frequent colds. Interestingly, the variables associated with cold frequency differed between women and men.

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Objectives Viral respiratory infections cause considerable morbidity and economic loss. While rhinoviruses (RV) typically cause little more than the common cold, they can produce severe infections and disease exacerbations in susceptible individuals, such as those with asthma. Variations in the regulation of key antiviral cytokines, particularly type I interferon (IFN‐α and IFN‐β), may contribute to RV susceptibility. To understand this variability, we compared the transcriptomes of high and low type I IFN producers. Methods Blood mononuclear cells from 238 individuals with or without asthma were cultured in the presence or absence of RV. Those samples demonstrating high or low RV‐stimulated IFN‐α production (N = 75) underwent RNA‐sequencing. Results Gene expression patterns were similar in samples from healthy participants and those with asthma. At baseline, the high IFN‐α producer group showed higher expression of genes associated with plasmacytoid dendritic cells, the innate immune response and vitamin D activation, but lower expression of oxidative stress pathways than the low IFN‐α producer group. After RV stimulation, the high IFN‐α producer group showed higher expression of genes found in immune response biological pathways and lower expression of genes linked to developmental and catabolic processes when compared to the low IFN‐α producer group. Conclusions These differences suggest that the high IFN‐α group has a higher level of immune system readiness, resulting in a more intense and perhaps more focussed pathogen‐specific immune response. These results contribute to a better understanding of the variability in type I IFN production between individuals.

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