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1. A soft-water stream iti upland Wales was dosed with sulphuric acid and aluminiutn sulphate at two successive points to create sitnultaneous episodes of low pH, and low pH with increased aluminiutn. Chemical atid biological responses were measured before, during and after the episode and were compared with a reference zotie.2. The pH fell frotn --7.0 to 4.28 (±0.18 SD) atid 5.02 {±0.10} respectively in the acid and aluminium zones. Corresponding aluminium concentrations during the episode were 0.052 g Al m"' (±0.008) and 0.347 g Al m^' (±0.047), the former not differing significantly from the reference zone. The concentration of cadmium rose to 0.002-0.011 g Cd m"^ in both treated areas, but the concentrations of other metals were unchanged.3. In situ toxicity tests were performed with macroinvertebrates and fish. Chironomus riparius. Hydropsyche angustipennis and Dinocras cephalotes suffered no mortality. Ecdyonurus venosus, Baetis rhodani and Gammarus pulex showed up to 25% mortality in both treatment zones and further mortalities occurred after the episode. Brown trout Salmo trutta and salmon .Va/mo,yfl/ar showed 7-10% mortality in the acid zone, but 50-87% in the aluminium zone, where salmon had a significantly shorter LTj,, than trout.4. The drift of Simuliidae increased during treatment in both acid and aluminium zones. Drift densities of Dixa puherula, Protonemura meyeri, Ephemeralla ignita and Dicranota sp. increased in the aluminium zone. The most pronounced response was by Baetis rhodani in the aluminium zone where drift density increased by x8.4 during the episode. 5. Baetis rhodani was the only taxon to show a significant decline in benthic density during the treatment, and then only in the aluminium zone. Drift could account for most of the losses.6. The depth distribution of invertebrates in the substratum differed between zones following treatment. More individuals were present at the surface of the reference zone (1287 m"-±747) than at the surface of the

1. Macroinvertebrates were sampled from three habitats at forty-five sites in the catchment of the Welsh River Wye. Species assemblages were ordinated by DECORANA. classified by TWIN-SPAN and related to physico-chemical factors using correlation and multiple discriminant analysis respectively.2. DECORANA axis 1 was correlated with pH or total hardness, whilst axis 2 correlated with slope or distance from source. TWINSPAN groupings were also related to hardness and. to a lesser extent, slope. Assemblages at soft-water sites (<15 g m"^ CaCO,) were composed mostly of Plecoptera but at hard-water sites, even at high slope (>iO m km"'), the fauna was dominated numerically by Ephemeroptera. net-spinning Trichoptera. Mollusca and Crustacea.3. We suggest that our data do not support the River Continuum Concept unless there are modifications to allow for multiple gradients.

Cancer stroma has a profound influence on tumor development and progression. The conversion of fibroblasts to activated myofibroblasts is a hallmark of reactive tumor stroma. Among a number of factors involved in this conversion, TGF-β has emerged as a major regulator. CLIC4, an integral protein in TGF-β signaling, is highly upregulated in stroma of multiple human cancers, and overexpression of CLIC4 in stromal cells enhances the growth of cancer xenografts. In this study we show that conditioned media from tumor cell lines induces expression of both CLIC4 and the myofibroblast marker alpha smooth muscle actin (α-SMA) in stromal fibroblasts via TGF-β signaling. Genetic ablation of CLIC4 in primary fibroblasts prevents or reduces constitutive or TGF-β induced expression of α-SMA and extracellular matrix components that are markers of myofibroblasts. CLIC4 is required for the activation of p38 Map Kinase by TGF-β, a pathway that signals myofibroblast conversion in stromal cells. This requirement involves the interaction of CLIC4 with PPM1a, the selective phosphatase of activated p-38. Conditioned media from fibroblasts overexpressing CLIC4 increases tumor cell migration and invasion in a TGF-β dependent manner and promotes epithelial to mesenchymal transition indicating that high stromal CLIC4 serves to enhance tumor invasiveness and progression. Thus, CLIC4 is significantly involved in the development of a nurturing tumor microenvironment by enhancing TGF-β signaling in a positive feedback loop. Targeting CLIC4 in tumor stroma should be considered as a strategy to mitigate some of the tumor enhancing effects of the cancer stroma.